Age-Related Macular Degeneration

Complex MONDO:0005150 Pathograph 30 Show in embeddings browser Ophthalmological Disease

Age-related macular degeneration (AMD) is a multifactorial disease of the macula in which age, smoking, and polygenic susceptibility converge on retinal pigment epithelial stress, dysregulated complement-mediated para-inflammation, outer-retinal extracellular deposits, and photoreceptor degeneration. Advanced dry AMD manifests as geographic atrophy, whereas wet AMD is driven by macular neovascularization with intraretinal or subretinal exudative injury. Both pathways can impair central vision.

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Classifications

Harrison's Part
NEUROLOGIC
👪

Inheritance

1
Polygenic inheritance HP:0010982
AMD risk is distributed across many loci rather than transmitted as a single Mendelian locus. A genome-wide association study of 16,144 patients and 17,832 controls identified 52 independently associated common and rare variants across 34 loci, and found that the dry and neovascular forms share most of their genetics. Very rare coding variants at a few of those loci are read by that study as identifying the causal gene, so the architecture is polygenic with a rare-variant component rather than common-variant polygenicity alone.
Polygenic inheritance
Show evidence (3 references)
PMID:26691988 SUPPORT Human clinical
"Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants ... distributed across 34 loci."
Establishes the cohort size, the variant count and the locus count quoted in the description, and so that AMD susceptibility is carried by many independent variants rather than one locus. The elision skips the genome-wide significance threshold, which is typeset with a multiplication sign and a superscript.
PMID:26691988 SUPPORT Human clinical
"Although wet and dry AMD subtypes exhibit predominantly shared genetics"
Supports treating the polygenic architecture as shared across the two clinical forms rather than stratifying inheritance by subtype.
PMID:26691988 SUPPORT Human clinical
"Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8."
Supports the rare-variant component of the architecture alongside the common-variant background.
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Subtypes

2
Dry AMD (Atrophic) MONDO:0100114
The non-neovascular form, with gradual outer-retinal degeneration that can progress to geographic atrophy.
Show evidence (1 reference)
PMID:38928273 SUPPORT Other
"This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form."
The review distinguishes the gradual dry course from the acute exudative form.
Wet AMD (Neovascular) MONDO:0005417
The exudative neovascular form, characterized by macular neovascularization with subretinal and/or intraretinal exudation and potentially rapid visual decline.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
The review defines exudative neovascular AMD by neovascularization and retinal exudation.
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Pathophysiology

9
Complement-Pathway Genetic Susceptibility
Common variation at CFH and in other complement-pathway genes, including C3 and CFB, alters susceptibility to AMD. CFB is not modeled as uniformly risk-increasing because human haplotype studies identify both risk and protective complement-region haplotypes. Very rare coding variants in CFH and in CFI, the complement factor I gene, carry the additional weight of identifying the causal gene within its locus rather than only tagging it.
CFH hgnc:4883 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFH (hgnc:4883). hgnc:4883 is a gene from the HUGO Gene Nomenclature Committee. C3 hgnc:1318 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves C3 (hgnc:1318). hgnc:1318 is a gene from the HUGO Gene Nomenclature Committee. CFB hgnc:1037 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFB (hgnc:1037). hgnc:1037 is a gene from the HUGO Gene Nomenclature Committee. CFI hgnc:5394 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFI (hgnc:5394). hgnc:5394 is a gene from the HUGO Gene Nomenclature Committee.
complement activation GO:0006956 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves complement activation (GO:0006956). GO:0006956 is a biological process from the Gene Ontology.
Downstream
Complement-Mediated Para-inflammation Complement-pathway susceptibility is placed upstream of dysregulated local complement activity, but the intervening genotype-to-tissue mechanisms are incompletely resolved.
Show evidence (4 references)
DOI:10.3390/biomedicines12071479 SUPPORT Other
"The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
The review supports CFH as a major common AMD susceptibility locus.
PMID:17634448 SUPPORT Human clinical
"The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish..."
Replicated case-control association supports C3 as a human AMD susceptibility gene.
PMID:16518403 SUPPORT Human clinical
"Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes."
Human haplotype data support a mixed risk/protective association at the CFB/C2 region.
+ 1 more reference
10q26 ARMS2/HTRA1 Genetic Susceptibility
Common variants at the chromosome 10q26 ARMS2/HTRA1 locus confer AMD susceptibility. The association is modeled at both candidate genes without selecting one causal gene or assigning an unsupported downstream molecular mechanism.
ARMS2 hgnc:32685 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ARMS2 (hgnc:32685). hgnc:32685 is a gene from the HUGO Gene Nomenclature Committee. HTRA1 hgnc:9476 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HTRA1 (hgnc:9476). hgnc:9476 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
DOI:10.3390/biomedicines12071479 SUPPORT Other
"The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
The review identifies the 10q26 ARMS2/HTRA1 locus while leaving causal-gene attribution unresolved.
RPE Oxidative and Lysosomal Stress
Age-related photo-oxidative products and reactive oxygen species stress retinal pigment epithelial cells. Protein-adduct formation and impaired autophagic flux compromise lysosomal clearance and cellular homeostasis.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. autophagy GO:0006914 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology.
Downstream
Complement-Mediated Para-inflammation Photo-oxidative lysosomal injury can activate complement and chronic inflammatory responses through protein-adduct formation and impaired autophagic clearance.
Photoreceptor Degeneration and Outer-Retinal Atrophy RPE injury and disrupted cellular homeostasis impair support of the outer retina and contribute to photoreceptor degeneration and atrophy.
Show evidence (2 references)
DOI:10.3390/antiox13050568 SUPPORT Other
"The toxic carbonyls due to photo-oxidative degradation of accumulated bisretinoids within lysosomes initiate a series of events including protein adduct formation, impaired autophagy flux, complement activation, and chronic inflammation, which is implicated in dry AMD."
The review links lysosomal bisretinoid photo-oxidation to adducts, impaired autophagy, complement activation, and inflammation in dry AMD.
DOI:10.3390/ijms26083463 SUPPORT Other
"A key contributor to disease progression is the excessive accumulation of reactive oxygen species (ROS), which damage retinal pigment epithelium (RPE) cells and disrupt cellular homeostasis."
The review directly supports ROS-mediated RPE damage and loss of homeostasis.
Complement-Mediated Para-inflammation
Dysregulated complement activation in the posterior eye contributes to chronic low-grade para-inflammation and, when poorly controlled, inflammatory tissue injury that can impair retinal integrity.
complement activation GO:0006956 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased complement activation (GO:0006956). GO:0006956 is a biological process from the Gene Ontology. inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Downstream
Photoreceptor Degeneration and Outer-Retinal Atrophy Chronic low-grade inflammation can exacerbate AMD tissue injury, although the complete set of intermediates leading to outer-retinal atrophy remains unresolved.
Show evidence (2 references)
PMID:38690727 SUPPORT Other
"Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis."
The review defines the complement-driven para-inflammatory process in the eye.
PMID:38690727 SUPPORT Other
"Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD)."
The review directly implicates complement dysregulation in AMD.
Outer-Retinal Extracellular Deposit Accumulation
Lipid-, complement-, amyloid-, and protein-containing extracellular deposits accumulate in the outer retina, including drusen beneath the retinal pigment epithelium. Drusen are a hallmark and progression marker, but are not treated here as a universally necessary or sufficient cause of advanced AMD.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
macula lutea UBERON:0000053 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in macula lutea (UBERON:0000053). UBERON:0000053 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Photoreceptor Degeneration and Outer-Retinal Atrophy Deposit accumulation precedes photoreceptor degeneration in the canonical AMD course, but the edge remains partial because drusen may also function as a biomarker and advanced AMD can occur without them.
Macular Drusen Outer-retinal deposit accumulation is clinically observed as macular drusen.
Show evidence (2 references)
PMID:38731137 SUPPORT Other
"Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others."
The review describes the location and heterogeneous composition of drusen.
PMID:38731137 SUPPORT Other
"Thus, there is the possibility that drusen might be no more than a biomarker of AMD and not a cause of AMD."
The review cautions against assuming that drusen are invariably causal.
Photoreceptor Degeneration and Outer-Retinal Atrophy
Degeneration of macular photoreceptors and loss of supporting retinal pigment epithelium produce outer-retinal atrophy; the advanced dry endpoint is geographic atrophy.
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology. retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
photoreceptor cell maintenance GO:0045494 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased photoreceptor cell maintenance (GO:0045494). GO:0045494 is a biological process from the Gene Ontology. retina homeostasis GO:0001895 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased retina homeostasis (GO:0001895). GO:0001895 is a biological process from the Gene Ontology.
macula lutea UBERON:0000053 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in macula lutea (UBERON:0000053). UBERON:0000053 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Macular Geographic Atrophy Advanced outer-retinal atrophy in dry AMD is termed geographic atrophy.
Central Vision Loss Macular photoreceptor degeneration impairs central vision.
Reduced Contrast Sensitivity Outer-retinal dysfunction can reduce contrast sensitivity, particularly in intermediate AMD and under low-light conditions.
Show evidence (2 references)
PMID:38193957 SUPPORT Human clinical
"AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision."
The review identifies photoreceptor degeneration as a central AMD tissue outcome.
PMID:38193957 SUPPORT Human clinical
"The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
The review identifies outer-retinal geographic atrophy as an advanced AMD endpoint.
VEGF-Driven Macular Neovascularization
Localized ischemia and inflammation increase VEGF production by retinal pigment epithelial and/or Mueller cells, promoting abnormal macular vascular growth from choriocapillaris or retinal microvascular sources.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology. Mueller cell CL:0000636 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Mueller cell (CL:0000636). CL:0000636 is a cell type from the Cell Ontology. retinal blood vessel endothelial cell CL:0002585 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal blood vessel endothelial cell (CL:0002585). CL:0002585 is a cell type from the Cell Ontology.
vascular endothelial growth factor production GO:0010573 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased vascular endothelial growth factor production (GO:0010573). GO:0010573 is a biological process from the Gene Ontology. angiogenesis GO:0001525 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology.
macula lutea UBERON:0000053 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in macula lutea (UBERON:0000053). UBERON:0000053 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Subretinal/Intraretinal Exudative Injury Fragile macular neovascular complexes produce intraretinal thickening and subretinal exudation.
Choroidal Neovascularization Neovascular wet AMD includes abnormal vessels arising from the choriocapillaris and presenting clinically as choroidal neovascularization.
Show evidence (1 reference)
PMID:39222802 SUPPORT Human clinical
"Neovascularization of the macula, a common complication of many chorioretinal diseases such as neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, and pathologic myopia, results from increased synthesis of vascular endothelial growth factor (VEGF) by the retinal..."
The review identifies localized ischemia/inflammation, RPE or Müller-cell VEGF production, and macular neovascularization.
Subretinal/Intraretinal Exudative Injury
Macular neovascular lesions disrupt outer-retinal architecture through intraretinal thickening and subretinal or intraretinal exudation, producing distortion, central field defects, and central visual loss.
macula lutea UBERON:0000053 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in macula lutea (UBERON:0000053). UBERON:0000053 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Metamorphopsia Exudative disruption of macular architecture distorts central vision.
Central Scotoma Exudative macular injury can produce a relative central scotoma.
Central Vision Loss Exudative damage to the macula reduces central vision.
Show evidence (1 reference)
PMID:39222802 SUPPORT Human clinical
"MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
The review links the exudative lesion to central visual symptoms and field defects.
Bruch Membrane Protein Homeostasis Gene Variation
Mechanism confidence: Provisional
Variation in three genes whose products act on extracellular protein homeostasis at Bruch's membrane contributes to AMD susceptibility. Rare missense variants in FBLN5, a member of the fibulin gene family, were found only in AMD cases in a screen of five fibulin genes, and every carrier had cuticular drusen. CST3 encodes cystatin C, a cysteine proteinase inhibitor abundantly secreted by the retinal pigment epithelium and proposed to regulate protein turnover in Bruch's membrane; its AMD risk variant is secreted at reduced levels. TIMP3 is constitutively expressed by retinal pigment epithelium, resides in Bruch's membrane in healthy eyes where it regulates the membrane's thickness by inhibiting matrix metalloproteinases, and is implicated in AMD by rare coding variants. The node groups the three by the compartment they act in, and does not claim that they converge on one molecular step.
FBLN5 hgnc:3602 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FBLN5 (hgnc:3602). hgnc:3602 is a gene from the HUGO Gene Nomenclature Committee. CST3 hgnc:2475 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CST3 (hgnc:2475). hgnc:2475 is a gene from the HUGO Gene Nomenclature Committee. TIMP3 hgnc:11822 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TIMP3 (hgnc:11822). hgnc:11822 is a gene from the HUGO Gene Nomenclature Committee.
Bruch's membrane UBERON:0003957 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Bruch's membrane (UBERON:0003957). UBERON:0003957 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Outer-Retinal Extracellular Deposit Accumulation Variation in these genes is placed upstream of extracellular deposit accumulation because the FBLN5 carriers are defined clinically by cuticular drusen and the CST3 risk variant reduces secretion of a protease inhibitor into the same compartment. The steps between genotype and deposit composition are not resolved.
Show evidence (6 references)
PMID:15269314 SUPPORT Human clinical
"Seven of the 402 patients with AMD had amino acid-altering sequence variations in the fibulin 5 gene, whereas none were observed among 429 control subjects"
Case-control evidence that rare FBLN5 coding variation contributes to AMD.
PMID:24458156 SUPPORT In vitro / ex vivo
"Cystatin C, a potent cysteine proteinase inhibitor, is abundantly secreted by the RPE and may contribute to regulating protein turnover in the Bruch's membrane (BrM)."
Places cystatin C, the CST3 product, in Bruch's membrane protein turnover, which is the compartment this node names.
PMID:24458156 SUPPORT In vitro / ex vivo
"A cystatin C variant associated with increased risk of developing AMD and Alzheimer's disease (AD) presents reduced secretion levels from RPE."
Gives the cellular consequence of the CST3 risk variant that links genotype to this compartment.
+ 3 more references
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Age-Related Macular Degeneration Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Central Vision Loss Eye HP:0000572 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Central vision loss, annotated with Visual loss (HP:0000572). HP:0000572 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision."
The review identifies central vision loss as a clinical consequence of AMD degeneration.
Metamorphopsia Eye HP:0012508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metamorphopsia (HP:0012508). HP:0012508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39222802 SUPPORT Human clinical
"MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
The review directly reports metamorphopsia with exudative MNV.
Central Scotoma Eye HP:0000603 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Central scotoma (HP:0000603). HP:0000603 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39222802 SUPPORT Human clinical
"MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
The review directly reports relative central scotoma with exudative MNV.
Reduced Contrast Sensitivity Eye HP:0032036 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced contrast sensitivity (HP:0032036). HP:0032036 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34412522 SUPPORT Human clinical
"Group differences in CS were only found in intermediate AMD patients. The loss in CS increased for the intermediate AMD patients under low light levels."
The study supports the phenotype in intermediate AMD while showing that it does not discriminate early AMD.
Macular Drusen Eye HP:0030499 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macular drusen (HP:0030499). HP:0030499 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38731137 SUPPORT Other
"In fact, it is well established that drusen are the hallmark of precursor lesion of AMD and a major risk factor for AMD progression mainly based on their size and number."
The review supports macular drusen as a hallmark precursor lesion and progression marker.
Macular Geographic Atrophy Eye HP:0031609 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macular geographic atrophy (HP:0031609). HP:0031609 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
The review defines geographic atrophy as an advanced outer-retinal AMD phenotype.
Choroidal Neovascularization Eye HP:0011506 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choroidal neovascularization (HP:0011506). HP:0011506 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
The review supports neovascularization as the defining lesion of wet AMD.
🧬

Genetic Associations

14
CFH (Common polygenic susceptibility locus)
Gene: CFH hgnc:4883 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFH (hgnc:4883). hgnc:4883 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
DOI:10.3390/biomedicines12071479 SUPPORT Other
"The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
The review identifies common CFH-region variants as an AMD susceptibility locus.
ARMS2 (Common susceptibility locus at 10q26)
Gene: ARMS2 hgnc:32685 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ARMS2 (hgnc:32685). hgnc:32685 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
DOI:10.3390/biomedicines12071479 SUPPORT Other
"The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
The review identifies ARMS2 at the common 10q26 AMD susceptibility locus.
HTRA1 (Common susceptibility locus at 10q26)
Gene: HTRA1 hgnc:9476 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HTRA1 (hgnc:9476). hgnc:9476 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
DOI:10.3390/biomedicines12071479 SUPPORT Other
"The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
The review identifies HTRA1 at the common 10q26 AMD susceptibility locus.
C3 (Common complement-pathway susceptibility variant)
Gene: C3 hgnc:1318 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is C3 (hgnc:1318). hgnc:1318 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:17634448 SUPPORT Human clinical
"The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish..."
Replication in two human case-control cohorts supports C3 susceptibility.
CFB (Complement-region susceptibility with both risk and protective haplotypes)
Gene: CFB hgnc:1037 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFB (hgnc:1037). hgnc:1037 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (2 references)
PMID:16518403 SUPPORT Human clinical
"Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes."
Human haplotype analysis supports a mixed risk/protective association at the CFB/C2 locus.
PMID:16518403 SUPPORT Human clinical
"The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0.45 and 0.36, respectively)."
The protective BF/CFB haplotypes prevent oversimplifying the locus as risk-only.
CFI (Very rare coding variants in CFI, the complement factor I gene, were among the rare-variant signals in a genome-wide association study of 16,144 AMD patients and 17,832 controls, which read them as evidence that CFI itself is causal within its locus rather than a bystander of a common association.)
Gene: CFI hgnc:5394 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFI (hgnc:5394). hgnc:5394 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:26691988 SUPPORT Human clinical
"Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8."
The 16,144-case study identifies rare CFI coding variants as evidence for a causal role, which is what distinguishes this record from a tagged common variant at an unresolved locus.
TIMP3 (Very rare coding variants in TIMP3 were among the rare-variant signals taken as evidence of a causal role in a genome-wide association study of 16,144 AMD patients and 17,832 controls. TIMP3 is constitutively expressed by retinal pigment epithelium and resides in Bruch's membrane in healthy eyes, where it limits matrix metalloproteinase activity and so regulates the thickness of that membrane.)
Gene: TIMP3 hgnc:11822 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TIMP3 (hgnc:11822). hgnc:11822 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (3 references)
PMID:26691988 SUPPORT Human clinical
"Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8."
Names TIMP3 among the genes whose rare coding variants imply a causal role in AMD.
PMID:28847738 SUPPORT REVIEW SYNTHESIS Other
"TIMP3 is constitutively expressed by RPE cells and, in healthy eyes, resides in Bruch's membrane."
Locates the TIMP3 protein in the compartment this entry wires the gene to. Graded as review synthesis because the review is summarising work it did not perform.
PMID:28847738 SUPPORT REVIEW SYNTHESIS Other
"An important function of TIMP3 within the outer retina is to regulate the thickness of Bruch's membrane. TIMP3 performs this function by inhibiting the activity of matrix metalloproteinases (MMPs), which have the function of catalysing breakdown of the extracellular matrix."
Supports the metalloproteinase-inhibition function attributed to TIMP3 in this record.
FBLN5 (Rare amino-acid-altering variants in FBLN5 (fibulin 5), one of five fibulin family genes screened in the reported series, were found in 1.7% of AMD cases and in none of the controls. All seven carriers had small circular drusen of the basal laminar or cuticular type, so this gene is associated with a specific deposit phenotype rather than with AMD in general.)
Gene: FBLN5 hgnc:3602 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FBLN5 (hgnc:3602). hgnc:3602 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (2 references)
PMID:15269314 SUPPORT Human clinical
"Seven of the 402 patients with AMD had amino acid-altering sequence variations in the fibulin 5 gene, whereas none were observed among 429 control subjects"
Case-control counts behind the FBLN5 association, in the clinic population from which both groups were drawn.
PMID:15269314 SUPPORT Human clinical
"these seven patients all had small, circular drusen, which are commonly referred to as basal laminar or cuticular drusen"
Ties the FBLN5 genotype to a particular drusen phenotype, which is why this gene is wired to the deposit node.
CST3 (The CST3 p.Ala25Thr variant, in the cysteine proteinase inhibitor cystatin C, is associated with exudative AMD with a recessive effect. Cystatin C is abundantly secreted by the retinal pigment epithelium and has been proposed to regulate protein turnover in Bruch's membrane, and the risk variant shows reduced secretion from retinal pigment epithelium, which is the mechanistic link this entry wires.)
Gene: CST3 hgnc:2475 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CST3 (hgnc:2475). hgnc:2475 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (2 references)
PMID:25893795 SUPPORT Human clinical
"Bringing together our data with the previously reported AMD-CST3 association study, the evidence of a recessive effect on AMD risk is strengthened (OR = 1.89, P = 0.005)."
Gives the combined recessive effect estimate for the CST3 variant in AMD.
PMID:24458156 SUPPORT In vitro / ex vivo
"A cystatin C variant associated with increased risk of developing AMD and Alzheimer's disease (AD) presents reduced secretion levels from RPE."
Supplies the cellular consequence of the risk variant that connects CST3 genotype to retinal pigment epithelium secretory function.
CX3CR1 (The CX3CR1 V249I and T280M variants have been proposed as AMD risk alleles, but two meta-analyses of the same two variants published in 2015 reached opposite conclusions, so the association is recorded here as contested rather than as susceptibility.)
Gene: CX3CR1 hgnc:2558 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CX3CR1 (hgnc:2558). hgnc:2558 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (2 references)
PMID:26305531 SUPPORT Human clinical
"Significant evidence for a relationship between T280M and V249I variants in CX3CR1 in the homozygote state with increased susceptibility to AMD was reported."
A meta-analysis of eight studies reporting a significant homozygote-state association.
PMID:26651305 REFUTE Human clinical
"This meta-analysis suggested that CX3CR1 T280M and V249I polymorphisms may not be associated with an increased risk of AMD based on current published data."
A meta-analysis of six studies of the same two variants finding no association, which is why the relationship is graded DISPUTED.
ABCA4 (ABCA4 was proposed as an AMD susceptibility gene on the basis of heterozygous variants in patients, the association behind the OMIM and MONDO "age related macular degeneration 2" designation. A survey that screened the whole gene in 200 individuals with late-stage AMD and in 220 unaffected individuals with the same methodology found no significant excess of candidate variants in cases, so this entry records the relationship as contested.)
Gene: ABCA4 hgnc:34 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ABCA4 (hgnc:34). hgnc:34 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (2 references)
PMID:10958763 SUPPORT Human clinical
"we have assessed the proposed role for ABCA4 in age-related macular degeneration (AMD), a common cause of late-onset blindness, by studying 200 affected individuals with late-stage disease"
Records that an ABCA4 role in AMD was a standing proposal, and that this study tested it by screening the whole gene in 200 individuals with late-stage AMD.
PMID:10958763 REFUTE Human clinical
"This represents no significant difference between the two groups"
The comparison of candidate ABCA4 alterations between 200 AMD cases and 220 controls found no excess in cases, which is the finding that puts the AMD association in dispute.
RAX2 (RAX2, originally described as QRX, was linked to macular degeneration by rare heterozygous sequence changes in three individuals with retinal degeneration, a finding the authors framed as raising a possibility. The gene's established disease associations are Mendelian inherited retinal disease: monoallelic variants in autosomal dominant cone-dominated retinal disease and biallelic variants in autosomal recessive retinitis pigmentosa.)
Gene: RAX2 hgnc:18286 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RAX2 (hgnc:18286). hgnc:18286 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (2 references)
PMID:15028672 SUPPORT INDIRECT Human clinical
"the finding of rare heterozygous QRX sequence changes in three individuals with retinal degeneration raises the possibility that QRX may be involved in disease pathogenesis"
The whole human genetic basis for a RAX2 retinal-degeneration association, stated by its authors as a possibility in three individuals and not specific to age-related macular degeneration.
PMID:30377383 NO_EVIDENCE Human clinical
"RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease."
Establishes the gene's recognised disease associations as Mendelian inherited retinal disease. It does not bear on an age-related macular degeneration association either way, which is the point: the AMD claim has not been revisited.
HMCN1 (The HMCN1 Gln5345Arg variant, reported in one large AMD family, is the basis of the OMIM and MONDO "age related macular degeneration 1" designation. Two later case-control studies in different populations found the variant in no subject at all, and one of them found no difference in the distribution of the polymorphism between cases and controls, so this entry records the relationship as contested.)
Gene: HMCN1 hgnc:19194 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HMCN1 (hgnc:19194). hgnc:19194 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (2 references)
PMID:17057786 REFUTE Human clinical
"The distribution of the Hemicentin-1 Q5345R, hOgg1 S326C, and E-selectin S149R SNPs did not differ significantly (all P values > .05) between the AMD patients and controls."
A case-control comparison in 89 advanced AMD patients against age-matched and unscreened controls found no association for the variant MONDO records for this term.
PMID:16885922 REFUTE Human clinical
"None of our subjects (258 AMD cases, 72 non-AMD controls) had the Gln5345Arg variant in the HMCN1 gene."
An independent population found the variant in none of 258 AMD cases, in the same study that replicated the CFH association strongly, so the negative result is not explained by an insensitive assay.
TLR4 (TLR4 rs4986790 (Asp299Gly) and rs4986791 (Thr399Ile) have been tested repeatedly against AMD risk, and are the variants behind the OMIM and MONDO "age related macular degeneration 10" designation. Two meta-analyses of overlapping study sets disagree: one reports rs4986790 as associated under recessive and overdominant models, the other finds that no TLR4 association survives correction for multiple testing. They do not disagree about the effect itself. Both report a nominal recessive-model odds ratio of 0.73 for rs4986790, and the dispute is only over whether that survives correction.)
Gene: TLR4 hgnc:11850 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TLR4 (hgnc:11850). hgnc:11850 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (2 references)
PMID:32102594 SUPPORT Human clinical
"The recessive and overdominant models showed that rs4986790 was significantly associated with AMD susceptibility, with odds ratios (ORs) of 0.73 and 1.41, respectively."
The positive side of the disagreement: a meta-analysis of six studies reporting an rs4986790 association under two of its four genetic models.
PMID:34287094 REFUTE Human clinical
"we found associations under the genotypic model of TLR4 c.896A>G ... although after Bonferroni correction (P'-value<0.02) none of these associations remained significant."
The negative side: a meta-analysis of the same two variants, in 12 case-control studies covering TLR4 and IL-8 together, finds that the nominal TLR4 associations, including the 0.73 odds ratio for rs4986790 (c.896A>G), do not survive multiple-testing correction.
💊

Medical Actions

5
Intravitreal Anti-VEGF Therapy
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Angiogenesis inhibitor NCIT:C1742 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Angiogenesis inhibitor (NCIT:C1742). NCIT:C1742 is a therapeutic agent from the NCI Thesaurus.
Intravitreal VEGF inhibition is first-line therapy for exudative neovascular AMD and preserves visual acuity relative to sham treatment.
Mechanism Target:
INHIBITS VEGF-Driven Macular Neovascularization — Anti-VEGF agents inhibit the VEGF-dependent neovascular pathway.
Show evidence (1 reference)
PMID:39222802 SUPPORT Human clinical
"The standard of care for MNV is usually intravitreal anti-vascular endothelial growth factor injections, though thermal laser photocoagulation, verteporfin photodynamic therapy, and vitreoretinal surgery are occasionally used."
The review identifies intravitreal anti-VEGF therapy as standard care for MNV.
Target Phenotypes: Choroidal Neovascularization HP:0011506 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Choroidal Neovascularization (HP:0011506). HP:0011506 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38193957 SUPPORT Human clinical
"Intravitreally administered anti-VEGF treatment is first-line therapy for exudative neovascular AMD."
The review identifies intravitreal anti-VEGF as first-line wet-AMD therapy.
PMID:38193957 SUPPORT Human clinical
"In exudative neovascular AMD, 94.6% of patients receiving monthly intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections experience less than a 15-letter visual acuity loss after 12 months compared with 62.2% receiving sham treatment."
The review reports controlled comparative evidence for preservation of visual acuity.
AREDS/AREDS2 Nutritional Supplementation
Category: Therapeutic Action: nutritional supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional supplementation, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
High-dose antioxidant vitamins, carotenoids, and zinc reduce progression to late-stage AMD in appropriately selected patients; this is not modeled as a direct correction of one molecular node.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"Individuals with AMD who take nutritional supplements consisting of high-dose vitamin C, vitamin E, carotenoids, and zinc have a 20% probability to progress to late-stage AMD at 5 years vs a 28% probability for those taking a placebo."
The review reports lower five-year progression with AREDS-type supplementation than placebo.
Complement-Inhibitor Therapy for Geographic Atrophy
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Complement inhibitor NCIT:C199456 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Complement inhibitor (NCIT:C199456). NCIT:C199456 is a therapeutic agent from the NCI Thesaurus.
Intravitreal complement inhibitors reduce geographic-atrophy lesion growth, but the cited network meta-analysis found no significant BCVA benefit and identified an increased macular-neovascularization risk with monthly pegcetacoplan.
Mechanism Target:
INHIBITS Complement-Mediated Para-inflammation — Complement inhibitors pharmacologically suppress the complement arm implicated in atrophic AMD.
Show evidence (1 reference)
DOI:10.3389/fphar.2024.1410172 SUPPORT Human clinical
"Clinical trials in recent years have shown significant effectiveness of complement inhibitors for geographic atrophy (GA) treatment."
The clinical-trial synthesis supports pharmacologic inhibition of the complement arm as a treatment strategy for GA.
Target Phenotypes: Macular Geographic Atrophy HP:0031609 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Macular Geographic Atrophy (HP:0031609). HP:0031609 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
DOI:10.3389/fphar.2024.1410172 SUPPORT Human clinical
"Comparison with sham and SUCRA analysis showed that avacincaptad pegol 2 mg (MD: −0.58, 95% CrI: −0.97 to −0.18, SUCRA: 93.55), pegcetacoplan monthly (MD: −0.38, 95% CrI: −0.57 to −0.20, SUCRA: 81.37), and pegcetacoplan every other month (MD: −0.30, 95% CrI: −0.49 to −0.11, SUCRA: 70.16) have..."
The network meta-analysis directly reports reduced geographic-atrophy lesion growth relative to sham.
DOI:10.3389/fphar.2024.1410172 SUPPORT Human clinical
"No treatments showed significant changes in BCVA and SAE compared with sham. Pegcetacoplan monthly (OR: 4.30, 95% CrI: 1.48–16.72) increased the risk of MNV."
The meta-analysis limits the benefit claim to anatomy and records the absence of BCVA improvement and an MNV safety signal.
Verteporfin Photodynamic Therapy
Category: Therapeutic Action: photodynamic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is photodynamic therapy (NCIT:C15300). NCIT:C15300 is a clinical intervention from the NCI Thesaurus. Ontology label: Photodynamic Therapy NCIT:C15300
Agent: verteporfin CHEBI:32293 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses verteporfin (CHEBI:32293). CHEBI:32293 is a therapeutic agent from Chemical Entities of Biological Interest.
Verteporfin photodynamic therapy is an occasional treatment option for selected macular neovascular lesions.
Target Phenotypes: Choroidal Neovascularization HP:0011506 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Choroidal Neovascularization (HP:0011506). HP:0011506 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39222802 SUPPORT Human clinical
"The standard of care for MNV is usually intravitreal anti-vascular endothelial growth factor injections, though thermal laser photocoagulation, verteporfin photodynamic therapy, and vitreoretinal surgery are occasionally used."
The review supports verteporfin photodynamic therapy as an occasional rather than standard MNV treatment.
Low-Vision Rehabilitation
Category: Therapeutic Action: RehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. NCIT:C15315
Low-vision aids and rehabilitation are recommended for geographic-atrophy-related visual loss.
Target Phenotypes: Central Vision Loss HP:0000572 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Central Vision Loss, annotated with Visual loss (HP:0000572). HP:0000572 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37455795 SUPPORT Human clinical
"Low vision patients with ARMD-related geographic atrophy should meet with low vision aids as soon as possible and should be included in low vision rehabilitation programs."
A human rehabilitation study supports early provision of low-vision aids and rehabilitation for geographic atrophy.
🌍

Environmental Factors

2
Older Age
AMD incidence rises steeply across older age strata.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"Older age, genetic factors, and environmental factors, such as cigarette smoking, are associated with development of AMD."
The review identifies older age as an AMD-associated factor.
Cigarette Smoking
exposure to cigarette smoking ECTO:0100003 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to cigarette smoking (ECTO:0100003). ECTO:0100003 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Long-term cigarette smoking is associated with higher AMD incidence.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked."
Prospective cohort evidence summarized in the review supports cigarette smoking as an environmental risk factor.
Mechanism Target:
PREDISPOSES RPE Oxidative and Lysosomal Stress — Pointed at retinal pigment epithelium oxidative and lysosomal stress because that is where this entry places the earliest acquired injury, and oxidative stress is the route by which smoking is understood to reach it. The intermediates are recorded as known on that mapped route rather than on the quoted sentence, which reaches only the disease. Predisposing rather than triggering because the item is an incidence comparison between smokers and never-smokers, which is a statement about risk.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked."
Long-term prospective cohorts showing significantly higher disease incidence in people smoking more than twenty cigarettes a day than in never-smokers. A dose-related incidence difference for the disease, which does not reach the retinal pigment epithelium at this node.
🔬

Diagnosis

3
Clinical Ophthalmic Examination
Primary diagnosis uses clinical ophthalmic examination with a special lens that focuses slit-lamp light through the pupil.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"AMD is diagnosed primarily with clinical examination that includes a special lens that focuses light of the slit lamp through the pupil."
The review describes the primary clinical ophthalmic examination used to diagnose AMD.
Optical Coherence Tomography
OCT identifies and characterizes exudative neovascular AMD and associated retinal fluid or thickening.
optical coherence tomography NCIT:C20828 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"Exudative neovascular AMD is best identified using angiography and by optical coherence tomography."
The review identifies OCT as a preferred diagnostic modality for exudative neovascular AMD.
Angiography
Dye-based or OCT angiography delineates macular neovascularization in wet AMD.
angiography NCIT:C190556 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"Exudative neovascular AMD is best identified using angiography and by optical coherence tomography."
The review identifies angiography as a preferred diagnostic modality for exudative neovascular AMD.
🩻

Imaging Findings

1
Macular neovascularization with intraretinal thickening and subretinal exudation on OCT
OCT can show a focal macular neovascular lesion with overlying intraretinal thickening and/or subretinal exudation, supporting diagnosis of wet AMD.
Modality: OCTOptical Coherence Tomography DiagnosticThis finding is pathognomonic or defines a diagnostic criterion Extent: FocalConfined to a single location or region Subtype: Wet AMD
Finding: Macular neovascularization with intraretinal thickening and subretinal exudation Location: macula lutea UBERON:0000053 Uberon multi-species anatomy ontology (UBERON) Phenotype: Choroidal neovascularization HP:0011506 Human Phenotype Ontology (HP)
Show evidence (2 references)
PMID:39222802 SUPPORT Human clinical
"MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
The review describes the focal macular lesion and its exudative imaging appearance.
PMID:39222802 SUPPORT Human clinical
"Neovascularization of the macula, a common complication of many chorioretinal diseases such as neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, and pathologic myopia, results from increased synthesis of vascular endothelial growth factor (VEGF) by the retinal..."
Restores the disease context, macular-neovascularization definition and lesion appearance before the imaging modalities. The source includes both retinal and choroidal vessel origins and does not equate all MNV with choroidal neovascularization.
📈

Progression

3
Early to intermediate extracellular-deposit stage
Outer-retinal extracellular deposits and macular drusen characterize early disease and predict progression, but drusen are not asserted as a universally causal lesion because advanced AMD can occur without them.
Show evidence (2 references)
PMID:38193957 SUPPORT Human clinical
"AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision."
The review places extracellular-deposit accumulation early in the AMD course.
PMID:38731137 SUPPORT Other
"Drusen are one of the most characteristic pathologies of precursor lesion of age-related macular degeneration (AMD). Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid,..."
Describes sub-RPE drusen, their precursor-stage and progression-risk associations, and advanced AMD without drusen, preserving uncertainty about causality.
Advanced geographic-atrophy stage
Dry AMD
Dry AMD progresses gradually to outer-retinal geographic atrophy with loss of photoreceptors and supporting retinal tissue.
Show evidence (2 references)
PMID:38193957 SUPPORT Human clinical
"The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
The review identifies geographic atrophy as an advanced AMD endpoint.
PMID:38928273 SUPPORT Other
"This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form."
The review characterizes dry AMD progression as slow and gradual.
Exudative neovascular stage
Wet AMD
Wet AMD may present with acute, severe progression as macular neovascularization produces intraretinal or subretinal exudation.
Show evidence (2 references)
PMID:38193957 SUPPORT Human clinical
"The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
The review defines the exudative neovascular late-stage pathway.
PMID:38928273 SUPPORT Other
"This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form."
The review characterizes wet AMD progression as acute and severe.
📊

Prevalence

2
People aged 55 to 59 years
Annual incidence 30.0 per 100,000 1–9 per 10,000 per year
Annual incidence reported as 0.3 per 1,000 people aged 55 to 59 years.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older."
The lower endpoint converts to 30 incident cases per 100,000 people per year.
People aged 90 years or older
Annual incidence 3670.0 per 100,000 >1 in 1,000 per year
Annual incidence reported as 36.7 per 1,000 people aged 90 years or older.
Show evidence (1 reference)
PMID:38193957 SUPPORT Human clinical
"The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older."
The upper endpoint converts to 3,670 incident cases per 100,000 people per year.
📊

Related Datasets

4
Non-canonical roles of CFH in retinal pigment epithelial cells revealed by dysfunctional rare CFH variants geo:GSE275494
Complement Factor H (CFH) common genetic variants have been associated with age-related macular degeneration (AMD). While most previous in vitro RPE studies focused on the common p.His402Tyr CFH variant, we characterized rare CFH variants that are highly penetrant for AMD using induced pluripotent stem cell derived retinal pigment epithelium (iPSC-RPE). Our results show that lower FH levels were detected in AMD RPE, which potentially disrupted canonical and non-canonical roles of FH. Specifically, AMD RPE displayed higher inflammation rate and a reduced set of differentially expressed genes compared to control RPE upon A2E and blue light challenge.
human BULK RNA SEQ n=90
PMID:39753135
Identified by GEO DataSets index search for Age-Related Macular Degeneration (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Human Plasma Metabolomics in Age-related Macular Degeneration (AMD) Using Nuclear Magnetic Resonance Spectroscopy metabolomics_workbench:ST000590
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Age-Related Macular Degeneration"). Retrieved 2026-08-02.
Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina massive:MSV000088713
Age-related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the loss of the retinal pigment epithelium (RPE) and photoreceptors and/or retinal and choroidal angiogenesis. Here we use AMD patient specific RPE cells with the Y402H high-risk polymorphism in the complement factor H to perform a comprehensive analysis of EVs, their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced and polarised EV secretion.
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Age-Related Macular Degeneration"). Retrieved 2026-08-02.
Genetics of Age-Related Macular Degeneration in the Amish dbgap:phs001361
Identifying genetic risk loci for Age-Related Macular Degeneration is important. Most of the loci identified to date have been found through the interrogation of common variants. This study initiates the identification of rare variants in a founder population, the Amish, and will use genotyping of known risk loci and ultimately use the whole exome chip to assess the association of Age-related Macular Degeneration with coding variants.
Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Age-Related Macular Degeneration"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Age-Related Macular Degeneration
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Age-related macular degeneration (AMD) is a multifactorial disease of the
  macula in which age, smoking, and polygenic susceptibility converge on
  retinal pigment epithelial stress, dysregulated complement-mediated
  para-inflammation, outer-retinal extracellular deposits, and photoreceptor
  degeneration. Advanced dry AMD manifests as geographic atrophy, whereas wet
  AMD is driven by macular neovascularization with intraretinal or subretinal
  exudative injury. Both pathways can impair central vision.
category: Complex
parents:
- Ophthalmological Disease
disease_term:
  preferred_term: age-related macular degeneration
  term:
    id: MONDO:0005150
    label: age-related macular degeneration
notes: >-
  Lump/split ruling for the MONDO subtype series filed under this entry. The
  "age related macular degeneration N" series (MONDO:0007932, MONDO:0012145,
  MONDO:0012419, MONDO:0012540, MONDO:0012659, MONDO:0012767, MONDO:0013406,
  MONDO:0013416, MONDO:0013420) consists of locus designations inherited from the
  OMIM phenotype series, not of clinically distinguishable gene-defined forms of
  disease. None is curated as a has_subtypes row here. Each named gene is curated
  instead as a genetic record with an explicit relationship_type, so a
  susceptibility allele is not presented as defining a subtype and a contested
  association is not presented as a susceptibility allele. The two clinical forms
  that AMD does split into, dry and neovascular, remain the has_subtypes rows, now
  anchored to MONDO:0100114 and MONDO:0005417.
  Enumerating the hierarchical children of MONDO:0005150 in OLS on 2026-09-24
  returns fifteen terms, five more than the ten this job was given. Two are the
  dry and neovascular forms just named. The other three are locus designations of
  the same series that carry no causal-gene edge in MONDO, which is why they are
  absent from a gene-keyed gap list: MONDO:0011285 (ARMD1, an HMCN1 variant),
  MONDO:0012674 (ARMD10, synonym "TLR4 age-related macular degeneration") and
  MONDO:0014207 (ARMD14, defined as variation at or near C2 and CFB). HMCN1 and
  TLR4 are curated here as DISPUTED genetic records with the case-control and
  meta-analytic evidence behind that ruling; the C2/CFB locus was already curated
  as a susceptibility record before this pass, so ARMD14 needs no new content.
  MONDO:0014515 "macular dystrophy with central cone involvement" is also filed
  as a child of age-related macular degeneration in MONDO, and is recorded there
  as equivalent to OMIM:616170. Its gene, MFSD8, is an autosomal recessive cause
  of nonsyndromic macular dystrophy (PMID:25227500) and is curated in this
  knowledge base as the gene of neuronal ceroid lipofuscinosis 7
  (kb/disorders/Neuronal_Ceroid_Lipofuscinosis_7.yaml). No subtype row or gene
  record is created for it here, because a recessive Mendelian macular dystrophy
  is a different disease from age-related macular degeneration rather than a form
  of it.
has_subtypes:
- name: Dry AMD
  display_name: Dry AMD (Atrophic)
  subtype_term:
    preferred_term: dry age related macular degeneration
    term:
      id: MONDO:0100114
      label: dry age related macular degeneration
  description: >-
    The non-neovascular form, with gradual outer-retinal degeneration that can
    progress to geographic atrophy.
  evidence:
  - reference: PMID:38928273
    reference_title: Immunogenetic and Environmental Factors in Age-Related Macular Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form."
    explanation: The review distinguishes the gradual dry course from the acute exudative form.
- name: Wet AMD
  display_name: Wet AMD (Neovascular)
  subtype_term:
    preferred_term: wet age related macular degeneration
    term:
      id: MONDO:0005417
      label: wet macular degeneration
  description: >-
    The exudative neovascular form, characterized by macular neovascularization
    with subretinal and/or intraretinal exudation and potentially rapid visual
    decline.
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
    explanation: The review defines exudative neovascular AMD by neovascularization and retinal exudation.
prevalence:
- population: People aged 55 to 59 years
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 30.0
  notes: Annual incidence reported as 0.3 per 1,000 people aged 55 to 59 years.
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older."
    explanation: The lower endpoint converts to 30 incident cases per 100,000 people per year.
- population: People aged 90 years or older
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 3670.0
  notes: Annual incidence reported as 36.7 per 1,000 people aged 90 years or older.
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The annual incidence of AMD ranges from 0.3 per 1000 in people who are aged 55 to 59 years to 36.7 per 1000 in people aged 90 years or older."
    explanation: The upper endpoint converts to 3,670 incident cases per 100,000 people per year.
progression:
- phase: Early to intermediate extracellular-deposit stage
  notes: >-
    Outer-retinal extracellular deposits and macular drusen characterize early
    disease and predict progression, but drusen are not asserted as a universally
    causal lesion because advanced AMD can occur without them.
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision."
    explanation: The review places extracellular-deposit accumulation early in the AMD course.
  - reference: PMID:38731137
    reference_title: Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Drusen are one of the most characteristic pathologies of precursor lesion of age-related
      macular degeneration (AMD). Drusen comprise a yellowish white substance that accumulates
      typically under the retinal pigment epithelium (RPE), and their constituents are lipids,
      complement, amyloid, crystallin, and others. In the past, many researchers have focused on
      drusen and tried to elucidate the pathophysiology of AMD because they believed that disease
      progression from early AMD to advanced AMD might be based on drusen or drusen might cause AMD.
      In fact, it is well established that drusen are the hallmark of precursor lesion of AMD and a
      major risk factor for AMD progression mainly based on their size and number. However, the
      existence of advanced AMD without drusen has long been recognized. For example, polypoidal
      choroidal vasculopathy (PCV), which comprises the majority of AMD cases in Asians, often lacks
      drusen. Thus, there is the possibility that drusen might be no more than a biomarker of AMD
      and not a cause of AMD.
    explanation: >-
      Describes sub-RPE drusen, their precursor-stage and progression-risk associations, and
      advanced AMD without drusen, preserving uncertainty about causality.
- phase: Advanced geographic-atrophy stage
  subtype: Dry AMD
  notes: >-
    Dry AMD progresses gradually to outer-retinal geographic atrophy with loss
    of photoreceptors and supporting retinal tissue.
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
    explanation: The review identifies geographic atrophy as an advanced AMD endpoint.
  - reference: PMID:38928273
    reference_title: Immunogenetic and Environmental Factors in Age-Related Macular Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form."
    explanation: The review characterizes dry AMD progression as slow and gradual.
- phase: Exudative neovascular stage
  subtype: Wet AMD
  notes: >-
    Wet AMD may present with acute, severe progression as macular
    neovascularization produces intraretinal or subretinal exudation.
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
    explanation: The review defines the exudative neovascular late-stage pathway.
  - reference: PMID:38928273
    reference_title: Immunogenetic and Environmental Factors in Age-Related Macular Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This disease can occur in two clinical forms, i.e., dry (progression is slowly and gradually) and exudative (wet, progression is acute and severe), which usually started as dry form."
    explanation: The review characterizes wet AMD progression as acute and severe.
pathophysiology:
- name: Complement-Pathway Genetic Susceptibility
  description: >-
    Common variation at CFH and in other complement-pathway genes, including C3
    and CFB, alters susceptibility to AMD. CFB is not modeled as uniformly
    risk-increasing because human haplotype studies identify both risk and
    protective complement-region haplotypes. Very rare coding variants in CFH and
    in CFI, the complement factor I gene, carry the additional weight of
    identifying the causal gene within its locus rather than only tagging it.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFH
    term:
      id: hgnc:4883
      label: CFH
  - preferred_term: C3
    term:
      id: hgnc:1318
      label: C3
  - preferred_term: CFB
    term:
      id: hgnc:1037
      label: CFB
  - preferred_term: CFI
    term:
      id: hgnc:5394
      label: CFI
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
  evidence:
  - reference: DOI:10.3390/biomedicines12071479
    reference_title: Genetic Insights into Age-Related Macular Degeneration
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
    explanation: The review supports CFH as a major common AMD susceptibility locus.
  - reference: PMID:17634448
    reference_title: Complement C3 variant and the risk of age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5))."
    explanation: Replicated case-control association supports C3 as a human AMD susceptibility gene.
  - reference: PMID:16518403
    reference_title: Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes."
    explanation: Human haplotype data support a mixed risk/protective association at the CFB/C2 region.
  - reference: PMID:26691988
    reference_title: A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest
      causal roles for these genes, as does a splice variant in SLC16A8.
    explanation: >-
      Supports CFI as a complement-pathway gene with a causal role in AMD, and
      supports CFH itself at the rare-variant level rather than only as a tagged
      common locus.
  downstream:
  - target: Complement-Mediated Para-inflammation
    description: >-
      Complement-pathway susceptibility is placed upstream of dysregulated local
      complement activity, but the intervening genotype-to-tissue mechanisms are
      incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered regulation of alternative complement activity
    evidence:
    - reference: PMID:38690727
      reference_title: "Complement regulation in the eye: implications for age-related macular degeneration."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis."
      explanation: The review supports complement dysregulation as an upstream contributor to ocular para-inflammation, while not resolving variant-specific intermediates.
- name: 10q26 ARMS2/HTRA1 Genetic Susceptibility
  description: >-
    Common variants at the chromosome 10q26 ARMS2/HTRA1 locus confer AMD
    susceptibility. The association is modeled at both candidate genes without
    selecting one causal gene or assigning an unsupported downstream molecular
    mechanism.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ARMS2
    term:
      id: hgnc:32685
      label: ARMS2
  - preferred_term: HTRA1
    term:
      id: hgnc:9476
      label: HTRA1
  evidence:
  - reference: DOI:10.3390/biomedicines12071479
    reference_title: Genetic Insights into Age-Related Macular Degeneration
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
    explanation: The review identifies the 10q26 ARMS2/HTRA1 locus while leaving causal-gene attribution unresolved.
- name: RPE Oxidative and Lysosomal Stress
  description: >-
    Age-related photo-oxidative products and reactive oxygen species stress
    retinal pigment epithelial cells. Protein-adduct formation and impaired
    autophagic flux compromise lysosomal clearance and cellular homeostasis.
  biological_scale: CELLULAR
  subtypes:
  - Dry AMD
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  evidence:
  - reference: DOI:10.3390/antiox13050568
    reference_title: Antioxidants and Mechanistic Insights for Managing Dry Age-Related Macular Degeneration
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The toxic carbonyls due to photo-oxidative degradation of accumulated bisretinoids within lysosomes initiate a series of events including protein adduct formation, impaired autophagy flux, complement activation, and chronic inflammation, which is implicated in dry AMD."
    explanation: The review links lysosomal bisretinoid photo-oxidation to adducts, impaired autophagy, complement activation, and inflammation in dry AMD.
  - reference: DOI:10.3390/ijms26083463
    reference_title: "Role of Oxidative Stress and Inflammation in Age Related Macular Degeneration: Insights into the Retinal Pigment Epithelium (RPE)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A key contributor to disease progression is the excessive accumulation of reactive oxygen species (ROS), which damage retinal pigment epithelium (RPE) cells and disrupt cellular homeostasis."
    explanation: The review directly supports ROS-mediated RPE damage and loss of homeostasis.
  downstream:
  - target: Complement-Mediated Para-inflammation
    description: >-
      Photo-oxidative lysosomal injury can activate complement and chronic
      inflammatory responses through protein-adduct formation and impaired
      autophagic clearance.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - photo-oxidative degradation of accumulated bisretinoids
    - protein-adduct formation
    - impaired autophagic flux
    evidence:
    - reference: DOI:10.3390/antiox13050568
      reference_title: Antioxidants and Mechanistic Insights for Managing Dry Age-Related Macular Degeneration
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The toxic carbonyls due to photo-oxidative degradation of accumulated bisretinoids within lysosomes initiate a series of events including protein adduct formation, impaired autophagy flux, complement activation, and chronic inflammation, which is implicated in dry AMD."
      explanation: This states the known intermediate sequence connecting lysosomal oxidative injury to complement activation and chronic inflammation.
  - target: Photoreceptor Degeneration and Outer-Retinal Atrophy
    description: >-
      RPE injury and disrupted cellular homeostasis impair support of the outer
      retina and contribute to photoreceptor degeneration and atrophy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - RPE cellular damage
    - loss of outer-retinal homeostatic support
    evidence:
    - reference: DOI:10.3390/ijms26083463
      reference_title: "Role of Oxidative Stress and Inflammation in Age Related Macular Degeneration: Insights into the Retinal Pigment Epithelium (RPE)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A key contributor to disease progression is the excessive accumulation of reactive oxygen species (ROS), which damage retinal pigment epithelium (RPE) cells and disrupt cellular homeostasis."
      explanation: The review supports the RPE injury step, while the compressed edge omits downstream tissue-level intermediates.
- name: Complement-Mediated Para-inflammation
  description: >-
    Dysregulated complement activation in the posterior eye contributes to
    chronic low-grade para-inflammation and, when poorly controlled, inflammatory
    tissue injury that can impair retinal integrity.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:38690727
    reference_title: "Complement regulation in the eye: implications for age-related macular degeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis."
    explanation: The review defines the complement-driven para-inflammatory process in the eye.
  - reference: PMID:38690727
    reference_title: "Complement regulation in the eye: implications for age-related macular degeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD)."
    explanation: The review directly implicates complement dysregulation in AMD.
  downstream:
  - target: Photoreceptor Degeneration and Outer-Retinal Atrophy
    description: >-
      Chronic low-grade inflammation can exacerbate AMD tissue injury, although
      the complete set of intermediates leading to outer-retinal atrophy remains
      unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic inflammatory impairment of retinal integrity
    evidence:
    - reference: DOI:10.3390/ijms26083463
      reference_title: "Role of Oxidative Stress and Inflammation in Age Related Macular Degeneration: Insights into the Retinal Pigment Epithelium (RPE)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Additionally, immunosenescence and chronic low-grade inflammation exacerbate AMD pathology, further impairing retinal integrity."
      explanation: The review supports inflammatory aggravation of retinal injury but does not resolve every step to atrophy.
- name: Outer-Retinal Extracellular Deposit Accumulation
  description: >-
    Lipid-, complement-, amyloid-, and protein-containing extracellular deposits
    accumulate in the outer retina, including drusen beneath the retinal pigment
    epithelium. Drusen are a hallmark and progression marker, but are not treated
    here as a universally necessary or sufficient cause of advanced AMD.
  biological_scale: TISSUE
  locations:
  - preferred_term: macula lutea
    term:
      id: UBERON:0000053
      label: macula lutea
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  evidence:
  - reference: PMID:38731137
    reference_title: Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others."
    explanation: The review describes the location and heterogeneous composition of drusen.
  - reference: PMID:38731137
    reference_title: Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Thus, there is the possibility that drusen might be no more than a biomarker of AMD and not a cause of AMD."
    explanation: The review cautions against assuming that drusen are invariably causal.
  downstream:
  - target: Photoreceptor Degeneration and Outer-Retinal Atrophy
    description: >-
      Deposit accumulation precedes photoreceptor degeneration in the canonical
      AMD course, but the edge remains partial because drusen may also function as
      a biomarker and advanced AMD can occur without them.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - incompletely resolved deposit-associated outer-retinal injury
    evidence:
    - reference: PMID:38193957
      reference_title: "Age-Related Macular Degeneration: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision."
      explanation: The review places deposit accumulation upstream of photoreceptor degeneration.
    - reference: PMID:38731137
      reference_title: Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Thus, there is the possibility that drusen might be no more than a biomarker of AMD and not a cause of AMD."
      explanation: This caveat justifies partial support and unknown intermediates for the causal edge.
  - target: Macular Drusen
    description: Outer-retinal deposit accumulation is clinically observed as macular drusen.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38731137
      reference_title: Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others."
      explanation: The review directly describes the deposits represented by the macular-drusen phenotype.
- name: Photoreceptor Degeneration and Outer-Retinal Atrophy
  description: >-
    Degeneration of macular photoreceptors and loss of supporting retinal pigment
    epithelium produce outer-retinal atrophy; the advanced dry endpoint is
    geographic atrophy.
  biological_scale: TISSUE
  subtypes:
  - Dry AMD
  locations:
  - preferred_term: macula lutea
    term:
      id: UBERON:0000053
      label: macula lutea
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  - preferred_term: retina homeostasis
    term:
      id: GO:0001895
      label: retina homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision."
    explanation: The review identifies photoreceptor degeneration as a central AMD tissue outcome.
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
    explanation: The review identifies outer-retinal geographic atrophy as an advanced AMD endpoint.
  downstream:
  - target: Macular Geographic Atrophy
    description: Advanced outer-retinal atrophy in dry AMD is termed geographic atrophy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38193957
      reference_title: "Age-Related Macular Degeneration: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
      explanation: The review directly equates the advanced outer-retinal atrophy endpoint with geographic atrophy.
  - target: Central Vision Loss
    description: Macular photoreceptor degeneration impairs central vision.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38193957
      reference_title: "Age-Related Macular Degeneration: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision."
      explanation: The review directly connects photoreceptor degeneration with central vision loss.
  - target: Reduced Contrast Sensitivity
    description: >-
      Outer-retinal dysfunction can reduce contrast sensitivity, particularly in
      intermediate AMD and under low-light conditions.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired macular visual processing under low luminance
    evidence:
    - reference: PMID:34412522
      reference_title: Contrast Sensitivity in Early to Intermediate Age-Related Macular Degeneration (AMD).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Group differences in CS were only found in intermediate AMD patients. The loss in CS increased for the intermediate AMD patients under low light levels."
      explanation: The human study supports reduced contrast sensitivity in intermediate AMD but not in all stages.
- name: VEGF-Driven Macular Neovascularization
  description: >-
    Localized ischemia and inflammation increase VEGF production by retinal
    pigment epithelial and/or Mueller cells, promoting abnormal macular vascular
    growth from choriocapillaris or retinal microvascular sources.
  biological_scale: TISSUE
  subtypes:
  - Wet AMD
  locations:
  - preferred_term: macula lutea
    term:
      id: UBERON:0000053
      label: macula lutea
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  - preferred_term: Mueller cell
    term:
      id: CL:0000636
      label: Mueller cell
  - preferred_term: retinal blood vessel endothelial cell
    term:
      id: CL:0002585
      label: retinal blood vessel endothelial cell
  biological_processes:
  - preferred_term: vascular endothelial growth factor production
    term:
      id: GO:0010573
      label: vascular endothelial growth factor production
    modifier: INCREASED
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
  evidence:
  - reference: PMID:39222802
    reference_title: Macular neovascularization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neovascularization of the macula, a common complication of many chorioretinal diseases such as neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, and pathologic myopia, results from increased synthesis of vascular endothelial growth factor (VEGF) by the retinal pigment epithelium and/or Müller cells because of localized ischemia and inflammation."
    explanation: The review identifies localized ischemia/inflammation, RPE or Müller-cell VEGF production, and macular neovascularization.
  downstream:
  - target: Subretinal/Intraretinal Exudative Injury
    description: Fragile macular neovascular complexes produce intraretinal thickening and subretinal exudation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39222802
      reference_title: Macular neovascularization.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
      explanation: The review directly describes exudative retinal injury overlying MNV.
  - target: Choroidal Neovascularization
    description: >-
      Neovascular wet AMD includes abnormal vessels arising from the
      choriocapillaris and presenting clinically as choroidal neovascularization.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38193957
      reference_title: "Age-Related Macular Degeneration: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
      explanation: The review supports neovascularization as the defining lesion of wet AMD.
- name: Subretinal/Intraretinal Exudative Injury
  description: >-
    Macular neovascular lesions disrupt outer-retinal architecture through
    intraretinal thickening and subretinal or intraretinal exudation, producing
    distortion, central field defects, and central visual loss.
  biological_scale: TISSUE
  subtypes:
  - Wet AMD
  locations:
  - preferred_term: macula lutea
    term:
      id: UBERON:0000053
      label: macula lutea
  evidence:
  - reference: PMID:39222802
    reference_title: Macular neovascularization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
    explanation: The review links the exudative lesion to central visual symptoms and field defects.
  downstream:
  - target: Metamorphopsia
    description: Exudative disruption of macular architecture distorts central vision.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - distortion of central retinal architecture
    evidence:
    - reference: PMID:39222802
      reference_title: Macular neovascularization.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
      explanation: The review explicitly links the exudative MNV lesion to metamorphopsia.
  - target: Central Scotoma
    description: Exudative macular injury can produce a relative central scotoma.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - localized macular dysfunction
    evidence:
    - reference: PMID:39222802
      reference_title: Macular neovascularization.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
      explanation: The review explicitly links the exudative MNV lesion to relative central scotoma.
  - target: Central Vision Loss
    description: Exudative damage to the macula reduces central vision.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - disruption of central retinal structure and function
    evidence:
    - reference: PMID:39222802
      reference_title: Macular neovascularization.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
      explanation: The review explicitly links the exudative MNV lesion to reduced central vision.
- name: Bruch Membrane Protein Homeostasis Gene Variation
  description: >-
    Variation in three genes whose products act on extracellular protein
    homeostasis at Bruch's membrane contributes to AMD susceptibility. Rare
    missense variants in FBLN5, a member of the fibulin gene family, were found
    only in AMD cases in a screen of five fibulin genes, and every carrier had
    cuticular drusen. CST3 encodes cystatin C, a cysteine proteinase inhibitor
    abundantly secreted by the retinal pigment epithelium and proposed to regulate
    protein turnover in Bruch's membrane; its AMD risk variant is secreted at
    reduced levels. TIMP3 is constitutively expressed by retinal pigment
    epithelium, resides in Bruch's membrane in healthy eyes where it regulates the
    membrane's thickness by inhibiting matrix metalloproteinases, and is
    implicated in AMD by rare coding variants. The node groups the three by the
    compartment they act in, and does not claim that they converge on one
    molecular step.
  biological_scale: MOLECULAR
  locations:
  - preferred_term: Bruch's membrane
    term:
      id: UBERON:0003957
      label: Bruch's membrane
  genes:
  - preferred_term: FBLN5
    term:
      id: hgnc:3602
      label: FBLN5
  - preferred_term: CST3
    term:
      id: hgnc:2475
      label: CST3
  - preferred_term: TIMP3
    term:
      id: hgnc:11822
      label: TIMP3
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:15269314
    reference_title: Missense variations in the fibulin 5 gene and age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven of the 402 patients with AMD had amino acid-altering sequence
      variations in the fibulin 5 gene, whereas none were observed among 429
      control subjects
    explanation: Case-control evidence that rare FBLN5 coding variation contributes to AMD.
  - reference: PMID:24458156
    reference_title: "Age-related changes of cystatin C expression and polarized secretion by retinal pigment epithelium: potential age-related macular degeneration links."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cystatin C, a potent cysteine proteinase inhibitor, is abundantly secreted
      by the RPE and may contribute to regulating protein turnover in the Bruch's
      membrane (BrM).
    explanation: Places cystatin C, the CST3 product, in Bruch's membrane protein turnover, which is the compartment this node names.
  - reference: PMID:24458156
    reference_title: "Age-related changes of cystatin C expression and polarized secretion by retinal pigment epithelium: potential age-related macular degeneration links."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A cystatin C variant associated with increased risk of developing AMD and
      Alzheimer's disease (AD) presents reduced secretion levels from RPE.
    explanation: Gives the cellular consequence of the CST3 risk variant that links genotype to this compartment.
  - reference: PMID:26691988
    reference_title: A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest
      causal roles for these genes, as does a splice variant in SLC16A8.
    explanation: Supports TIMP3 as a causal AMD gene implicated by rare coding variants.
  - reference: PMID:28847738
    reference_title: Sorsby fundus dystrophy - A review of pathology and disease mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "TIMP3 is constitutively expressed by RPE cells and, in healthy eyes, resides in Bruch's membrane."
    explanation: >-
      Places TIMP3 in Bruch's membrane, which is what justifies binding it to this
      node rather than to a generic susceptibility node.
  - reference: PMID:15269314
    reference_title: Missense variations in the fibulin 5 gene and age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA samples were screened for sequence variations in five members of the fibulin gene family."
    explanation: Supports describing FBLN5 as one of five fibulin family genes screened in that series.
  downstream:
  - target: Outer-Retinal Extracellular Deposit Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Variation in these genes is placed upstream of extracellular deposit
      accumulation because the FBLN5 carriers are defined clinically by cuticular
      drusen and the CST3 risk variant reduces secretion of a protease inhibitor
      into the same compartment. The steps between genotype and deposit
      composition are not resolved.
    intermediate_mechanisms:
    - altered extracellular protein turnover at Bruch's membrane
    evidence:
    - reference: PMID:15269314
      reference_title: Missense variations in the fibulin 5 gene and age-related macular degeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        these seven patients all had small, circular drusen, which are commonly
        referred to as basal laminar or cuticular drusen
      explanation: Every FBLN5 carrier in the series had a defined drusen phenotype, which is the deposit outcome this edge asserts.
phenotypes:
- name: Central Vision Loss
  category: Eye
  description: Progressive or acute loss of central visual function from macular outer-retinal injury.
  phenotype_term:
    preferred_term: Central vision loss
    term:
      id: HP:0000572
      label: Visual loss
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision."
    explanation: The review identifies central vision loss as a clinical consequence of AMD degeneration.
- name: Metamorphopsia
  category: Eye
  subtype: Wet AMD
  description: Distortion of visual images caused by neovascular exudative macular injury.
  phenotype_term:
    preferred_term: Metamorphopsia
    term:
      id: HP:0012508
      label: Metamorphopsia
  evidence:
  - reference: PMID:39222802
    reference_title: Macular neovascularization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
    explanation: The review directly reports metamorphopsia with exudative MNV.
- name: Central Scotoma
  category: Eye
  subtype: Wet AMD
  description: A central visual-field defect associated with macular neovascular injury.
  phenotype_term:
    preferred_term: Central scotoma
    term:
      id: HP:0000603
      label: Central scotoma
  evidence:
  - reference: PMID:39222802
    reference_title: Macular neovascularization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
    explanation: The review directly reports relative central scotoma with exudative MNV.
- name: Reduced Contrast Sensitivity
  category: Eye
  description: Reduced contrast discrimination, especially in intermediate AMD under low-light conditions.
  phenotype_term:
    preferred_term: Reduced contrast sensitivity
    term:
      id: HP:0032036
      label: Reduced contrast sensitivity
  evidence:
  - reference: PMID:34412522
    reference_title: Contrast Sensitivity in Early to Intermediate Age-Related Macular Degeneration (AMD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Group differences in CS were only found in intermediate AMD patients. The loss in CS increased for the intermediate AMD patients under low light levels."
    explanation: The study supports the phenotype in intermediate AMD while showing that it does not discriminate early AMD.
- name: Macular Drusen
  category: Eye
  description: Extracellular macular deposits, typically beneath the retinal pigment epithelium.
  diagnostic: true
  phenotype_term:
    preferred_term: Macular drusen
    term:
      id: HP:0030499
      label: Macular drusen
  evidence:
  - reference: PMID:38731137
    reference_title: Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In fact, it is well established that drusen are the hallmark of precursor lesion of AMD and a major risk factor for AMD progression mainly based on their size and number."
    explanation: The review supports macular drusen as a hallmark precursor lesion and progression marker.
- name: Macular Geographic Atrophy
  category: Eye
  subtype: Dry AMD
  description: Advanced dry AMD with geographic outer-retinal atrophy in the macula.
  diagnostic: true
  phenotype_term:
    preferred_term: Macular geographic atrophy
    term:
      id: HP:0031609
      label: Macular geographic atrophy
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
    explanation: The review defines geographic atrophy as an advanced outer-retinal AMD phenotype.
- name: Choroidal Neovascularization
  category: Eye
  subtype: Wet AMD
  description: Pathologic neovascular growth in the macula characteristic of neovascular AMD.
  diagnostic: true
  phenotype_term:
    preferred_term: Choroidal neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD."
    explanation: The review supports neovascularization as the defining lesion of wet AMD.
imaging_findings:
- name: Macular neovascularization with intraretinal thickening and subretinal exudation on OCT
  modality: OCT
  imaging_finding_term:
    preferred_term: Macular neovascularization with intraretinal thickening and subretinal exudation
  description: >-
    OCT can show a focal macular neovascular lesion with overlying intraretinal
    thickening and/or subretinal exudation, supporting diagnosis of wet AMD.
  located_in:
    preferred_term: macula lutea
    term:
      id: UBERON:0000053
      label: macula lutea
  spatial_extent: FOCAL
  phenotype_term:
    preferred_term: Choroidal neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  diagnostic: true
  subtype: Wet AMD
  evidence:
  - reference: PMID:39222802
    reference_title: Macular neovascularization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition."
    explanation: The review describes the focal macular lesion and its exudative imaging appearance.
  - reference: PMID:39222802
    reference_title: Macular neovascularization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neovascularization of the macula, a common complication of many chorioretinal diseases such as
      neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, and
      pathologic myopia, results from increased synthesis of vascular endothelial growth factor
      (VEGF) by the retinal pigment epithelium and/or Müller cells because of localized ischemia and
      inflammation. The Consensus on Neovascular AMD Nomenclature (CONAN) study group acknowledged
      that these vessels may originate from either the choriocapillaris or the retinal
      microvasculature, prompting them to propose the term 'macular neovascularization' (MNV) to
      include intraretinal, subretinal, and sub-pigment epithelial neovascularization localized to
      the macula. MNV frequently appears as a grey-green macular lesion with overlying intraretinal
      thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision,
      relative central scotoma, decreased reading speed, and problems with color recognition.
      Multimodal imaging with optical coherence tomography (OCT), OCT angiography, dye-based
      angiographies, fundus autofluorescence, and multiwavelength photography help establish the
      diagnosis and aid in selecting an appropriate treatment.
    explanation: >-
      Restores the disease context, macular-neovascularization definition and lesion appearance
      before the imaging modalities. The source includes both retinal and choroidal vessel origins
      and does not equate all MNV with choroidal neovascularization.
genetic:
- name: CFH
  gene_term:
    preferred_term: CFH
    term:
      id: hgnc:4883
      label: CFH
  association: Common polygenic susceptibility locus
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: DOI:10.3390/biomedicines12071479
    reference_title: Genetic Insights into Age-Related Macular Degeneration
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
    explanation: The review identifies common CFH-region variants as an AMD susceptibility locus.
- name: ARMS2
  gene_term:
    preferred_term: ARMS2
    term:
      id: hgnc:32685
      label: ARMS2
  association: Common susceptibility locus at 10q26
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    The 10q26 association spans ARMS2 and HTRA1; this record does not resolve
    which gene or downstream mechanism is causal.
  evidence:
  - reference: DOI:10.3390/biomedicines12071479
    reference_title: Genetic Insights into Age-Related Macular Degeneration
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
    explanation: The review identifies ARMS2 at the common 10q26 AMD susceptibility locus.
- name: HTRA1
  gene_term:
    preferred_term: HTRA1
    term:
      id: hgnc:9476
      label: HTRA1
  association: Common susceptibility locus at 10q26
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    The 10q26 association spans ARMS2 and HTRA1; this record does not resolve
    which gene or downstream mechanism is causal.
  evidence:
  - reference: DOI:10.3390/biomedicines12071479
    reference_title: Genetic Insights into Age-Related Macular Degeneration
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The common genetic variants linked to AMD are found on chromosome 1q32 (in the complement factor H gene) and 10q26 (age-related maculopathy susceptibility 2 and high-temperature requirement A serine peptidase 1 genes) loci, along with several other risk variants."
    explanation: The review identifies HTRA1 at the common 10q26 AMD susceptibility locus.
- name: C3
  gene_term:
    preferred_term: C3
    term:
      id: hgnc:1318
      label: C3
  association: Common complement-pathway susceptibility variant
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:17634448
    reference_title: Complement C3 variant and the risk of age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5))."
    explanation: Replication in two human case-control cohorts supports C3 susceptibility.
- name: CFB
  gene_term:
    preferred_term: CFB
    term:
      id: hgnc:1037
      label: CFB
  association: Complement-region susceptibility with both risk and protective haplotypes
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    The CFB/C2 region contains a common risk haplotype as well as protective
    haplotypes; CFB is therefore not represented as uniformly risk-increasing.
  evidence:
  - reference: PMID:16518403
    reference_title: Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes."
    explanation: Human haplotype analysis supports a mixed risk/protective association at the CFB/C2 locus.
  - reference: PMID:16518403
    reference_title: Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0.45 and 0.36, respectively)."
    explanation: The protective BF/CFB haplotypes prevent oversimplifying the locus as risk-only.
- name: CFI
  gene_term:
    preferred_term: CFI
    term:
      id: hgnc:5394
      label: CFI
  association: >-
    Very rare coding variants in CFI, the complement factor I gene, were among
    the rare-variant signals in a genome-wide association study of 16,144 AMD
    patients and 17,832 controls, which read them as evidence that CFI itself is
    causal within its locus rather than a bystander of a common association.
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:26691988
    reference_title: A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest
      causal roles for these genes, as does a splice variant in SLC16A8.
    explanation: >-
      The 16,144-case study identifies rare CFI coding variants as evidence for a
      causal role, which is what distinguishes this record from a tagged common
      variant at an unresolved locus.
- name: TIMP3
  gene_term:
    preferred_term: TIMP3
    term:
      id: hgnc:11822
      label: TIMP3
  association: >-
    Very rare coding variants in TIMP3 were among the rare-variant signals taken
    as evidence of a causal role in a genome-wide association study of 16,144 AMD
    patients and 17,832 controls. TIMP3 is constitutively expressed by retinal
    pigment epithelium and resides in Bruch's membrane in healthy eyes, where it
    limits matrix metalloproteinase activity and so regulates the thickness of
    that membrane.
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    TIMP3's Mendelian disease is Sorsby fundus dystrophy, which the cited review
    describes as an autosomal dominant macular dystrophy with onset around the
    fourth to sixth decade. It has no entry in this knowledge base. The record here rests on the AMD
    rare-variant burden result, not on the Sorsby literature; the Sorsby review is
    cited only for where the TIMP3 protein sits and what it does, which is what
    justifies binding the gene to the Bruch's membrane node.
  evidence:
  - reference: PMID:26691988
    reference_title: A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest
      causal roles for these genes, as does a splice variant in SLC16A8.
    explanation: Names TIMP3 among the genes whose rare coding variants imply a causal role in AMD.
  - reference: PMID:28847738
    reference_title: Sorsby fundus dystrophy - A review of pathology and disease mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "TIMP3 is constitutively expressed by RPE cells and, in healthy eyes, resides in Bruch's membrane."
    explanation: >-
      Locates the TIMP3 protein in the compartment this entry wires the gene to.
      Graded as review synthesis because the review is summarising work it did not
      perform.
  - reference: PMID:28847738
    reference_title: Sorsby fundus dystrophy - A review of pathology and disease mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      An important function of TIMP3 within the outer retina is to regulate the
      thickness of Bruch's membrane. TIMP3 performs this function by inhibiting
      the activity of matrix metalloproteinases (MMPs), which have the function of
      catalysing breakdown of the extracellular matrix.
    explanation: Supports the metalloproteinase-inhibition function attributed to TIMP3 in this record.
- name: FBLN5
  gene_term:
    preferred_term: FBLN5
    term:
      id: hgnc:3602
      label: FBLN5
  association: >-
    Rare amino-acid-altering variants in FBLN5 (fibulin 5), one of five fibulin
    family genes screened in the reported series, were found in 1.7% of AMD cases
    and in none of the controls. All seven carriers had small circular drusen of
    the basal laminar or cuticular type, so this gene is associated with a
    specific deposit phenotype rather than with AMD in general.
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:15269314
    reference_title: Missense variations in the fibulin 5 gene and age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven of the 402 patients with AMD had amino acid-altering sequence
      variations in the fibulin 5 gene, whereas none were observed among 429
      control subjects
    explanation: Case-control counts behind the FBLN5 association, in the clinic population from which both groups were drawn.
  - reference: PMID:15269314
    reference_title: Missense variations in the fibulin 5 gene and age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these seven patients all had small, circular drusen, which are commonly
      referred to as basal laminar or cuticular drusen
    explanation: Ties the FBLN5 genotype to a particular drusen phenotype, which is why this gene is wired to the deposit node.
  case_fractions:
  - population: AMD case series from a single clinic population (402 patients)
    case_fraction_percent: 1.7
    cohort_size: 402
    notes: >-
      Share of an AMD case series carrying an amino-acid-altering FBLN5 variant.
      The cohort is ascertained for AMD by ophthalmoscopy, slit-lamp microscopy
      and fundus photography.
    evidence:
    - reference: PMID:15269314
      reference_title: Missense variations in the fibulin 5 gene and age-related macular degeneration.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Missense mutations in the fibulin 5 gene were found in 1.7 percent of patients with AMD."
      explanation: States the case fraction directly.
- name: CST3
  gene_term:
    preferred_term: CST3
    term:
      id: hgnc:2475
      label: CST3
  association: >-
    The CST3 p.Ala25Thr variant, in the cysteine proteinase inhibitor cystatin C,
    is associated with exudative AMD with a recessive effect. Cystatin C is
    abundantly secreted by the retinal pigment epithelium and has been proposed to
    regulate protein turnover in Bruch's membrane, and the risk variant shows
    reduced secretion from retinal pigment epithelium, which is the mechanistic
    link this entry wires.
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    This is a candidate-gene association with a replication, not a genome-wide
    significant locus. The combined recessive estimate rests on 350 newly
    genotyped exudative AMD cases plus one previously published association
    study, so the effect size should be read as provisional.
  evidence:
  - reference: PMID:25893795
    reference_title: "A missense variant in CST3 exerts a recessive effect on susceptibility to age-related macular degeneration resembling its association with Alzheimer's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bringing together our data with the previously reported AMD-CST3
      association study, the evidence of a recessive effect on AMD risk is
      strengthened (OR = 1.89, P = 0.005).
    explanation: Gives the combined recessive effect estimate for the CST3 variant in AMD.
  - reference: PMID:24458156
    reference_title: "Age-related changes of cystatin C expression and polarized secretion by retinal pigment epithelium: potential age-related macular degeneration links."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A cystatin C variant associated with increased risk of developing AMD and
      Alzheimer's disease (AD) presents reduced secretion levels from RPE.
    explanation: Supplies the cellular consequence of the risk variant that connects CST3 genotype to retinal pigment epithelium secretory function.
- name: CX3CR1
  gene_term:
    preferred_term: CX3CR1
    term:
      id: hgnc:2558
      label: CX3CR1
  association: >-
    The CX3CR1 V249I and T280M variants have been proposed as AMD risk alleles,
    but two meta-analyses of the same two variants published in 2015 reached
    opposite conclusions, so the association is recorded here as contested rather
    than as susceptibility.
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  notes: >-
    MONDO:0013420 (age related macular degeneration 12) records CX3CR1 as a
    causal gene. This entry does not treat it as one and does not wire it into
    the pathograph, because the two 2015 meta-analyses of V249I and T280M
    disagree with each other.
  evidence:
  - reference: PMID:26305531
    reference_title: Associations Between the T280M and V249I SNPs in CX3CR1 and the Risk of Age-Related Macular Degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant evidence for a relationship between T280M and V249I variants in
      CX3CR1 in the homozygote state with increased susceptibility to AMD was
      reported.
    explanation: A meta-analysis of eight studies reporting a significant homozygote-state association.
  - reference: PMID:26651305
    reference_title: "Association of CX3CR1 (V249I and T280M) polymorphisms with age-related macular degeneration: a meta-analysis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This meta-analysis suggested that CX3CR1 T280M and V249I polymorphisms may
      not be associated with an increased risk of AMD based on current published
      data.
    explanation: A meta-analysis of six studies of the same two variants finding no association, which is why the relationship is graded DISPUTED.
- name: ABCA4
  gene_term:
    preferred_term: ABCA4
    term:
      id: hgnc:34
      label: ABCA4
  association: >-
    ABCA4 was proposed as an AMD susceptibility gene on the basis of heterozygous
    variants in patients, the association behind the OMIM and MONDO "age related
    macular degeneration 2" designation. A survey that screened the whole gene in
    200 individuals with late-stage AMD and in 220 unaffected individuals with the
    same methodology found no significant excess of candidate variants in cases,
    so this entry records the relationship as contested.
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  notes: >-
    ABCA4's established disease is Stargardt disease, curated separately as
    kb/disorders/Stargardt_Disease.yaml. MONDO:0007932 is filed as a child of
    age-related macular degeneration; this entry declines it as an AMD subtype
    rather than curating a subtype row for it. The negative study states its own
    limit: 18 of the AMD patients and 12 of the controls carried possible
    disease-associated alterations, and the authors add that detecting modest
    effects of rare alleles may require larger cohorts. DISPUTED therefore records
    a failed replication, not a demonstrated absence of effect.
  evidence:
  - reference: PMID:10958763
    reference_title: A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we have assessed the proposed role for ABCA4 in age-related macular
      degeneration (AMD), a common cause of late-onset blindness, by studying 200
      affected individuals with late-stage disease
    explanation: >-
      Records that an ABCA4 role in AMD was a standing proposal, and that this
      study tested it by screening the whole gene in 200 individuals with
      late-stage AMD.
  - reference: PMID:10958763
    reference_title: A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "This represents no significant difference between the two groups"
    explanation: >-
      The comparison of candidate ABCA4 alterations between 200 AMD cases and 220
      controls found no excess in cases, which is the finding that puts the AMD
      association in dispute.
- name: RAX2
  gene_term:
    preferred_term: RAX2
    term:
      id: hgnc:18286
      label: RAX2
  association: >-
    RAX2, originally described as QRX, was linked to macular degeneration by rare
    heterozygous sequence changes in three individuals with retinal degeneration,
    a finding the authors framed as raising a possibility. The gene's established
    disease associations are Mendelian inherited retinal disease: monoallelic
    variants in autosomal dominant cone-dominated retinal disease and biallelic
    variants in autosomal recessive retinitis pigmentosa.
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  notes: >-
    MONDO:0013406 (age related macular degeneration 6) records RAX2 as a causal
    gene. This entry declines it as an AMD subtype and does not wire RAX2 into
    the pathograph: the supporting observation is three individuals with
    unspecified retinal degeneration, and the subsequent RAX2 literature places
    the gene in inherited retinal dystrophy rather than in age-related macular
    degeneration.
  evidence:
  - reference: PMID:15028672
    reference_title: "QRX, a novel homeobox gene, modulates photoreceptor gene expression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      the finding of rare heterozygous QRX sequence changes in three individuals
      with retinal degeneration raises the possibility that QRX may be involved
      in disease pathogenesis
    explanation: >-
      The whole human genetic basis for a RAX2 retinal-degeneration association,
      stated by its authors as a possibility in three individuals and not
      specific to age-related macular degeneration.
  - reference: PMID:30377383
    reference_title: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RAX2 encodes a homeobox-containing transcription factor, in which four
      monoallelic pathogenic variants have been described in autosomal dominant
      cone-dominated retinal disease.
    explanation: >-
      Establishes the gene's recognised disease associations as Mendelian
      inherited retinal disease. It does not bear on an age-related macular
      degeneration association either way, which is the point: the AMD claim has
      not been revisited.
- name: HMCN1
  gene_term:
    preferred_term: HMCN1
    term:
      id: hgnc:19194
      label: HMCN1
  association: >-
    The HMCN1 Gln5345Arg variant, reported in one large AMD family, is the basis
    of the OMIM and MONDO "age related macular degeneration 1" designation. Two
    later case-control studies in different populations found the variant in no
    subject at all, and one of them found no difference in the distribution of the
    polymorphism between cases and controls, so this entry records the
    relationship as contested.
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  notes: >-
    MONDO:0011285 (age related macular degeneration 1) is a child of
    age-related macular degeneration and its definition names an HMCN1
    polymorphism at 1q25.3-q31.1, which is the gene's HGNC-recorded location. It
    is not in the reconciliation checklist for this job, because MONDO records no
    causal-gene edge for the term. This entry declines it as an AMD subtype and
    does not wire HMCN1 into the pathograph.
  evidence:
  - reference: PMID:17057786
    reference_title: "Analysis of Hemicentin-1, hOgg1, and E-selectin single nucleotide polymorphisms in age-related macular degeneration."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distribution of the Hemicentin-1 Q5345R, hOgg1 S326C, and E-selectin
      S149R SNPs did not differ significantly (all P values > .05) between the AMD
      patients and controls.
    explanation: >-
      A case-control comparison in 89 advanced AMD patients against age-matched
      and unscreened controls found no association for the variant MONDO records
      for this term.
  - reference: PMID:16885922
    reference_title: "Analysis of variants in the complement factor H, the elongation of very long chain fatty acids-like 4 and the hemicentin 1 genes of age-related macular degeneration in the Finnish population."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of our subjects (258 AMD cases, 72 non-AMD controls) had the Gln5345Arg
      variant in the HMCN1 gene.
    explanation: >-
      An independent population found the variant in none of 258 AMD cases, in the
      same study that replicated the CFH association strongly, so the negative
      result is not explained by an insensitive assay.
- name: TLR4
  gene_term:
    preferred_term: TLR4
    term:
      id: hgnc:11850
      label: TLR4
  association: >-
    TLR4 rs4986790 (Asp299Gly) and rs4986791 (Thr399Ile) have been tested
    repeatedly against AMD risk, and are the variants behind the OMIM and MONDO
    "age related macular degeneration 10" designation. Two meta-analyses of
    overlapping study sets disagree: one reports rs4986790 as associated under
    recessive and overdominant models, the other finds that no TLR4 association
    survives correction for multiple testing. They do not disagree about the
    effect itself. Both report a nominal recessive-model odds ratio of 0.73 for
    rs4986790, and the dispute is only over whether that survives correction.
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  notes: >-
    MONDO:0012674 (age related macular degeneration 10) is a child of
    age-related macular degeneration and carries "TLR4 age-related macular
    degeneration" as an exact synonym generated by MONDO's
    disease_series_by_gene design pattern; it records no causal-gene edge, so it
    is not in the reconciliation checklist for this job. This entry declines it
    as an AMD subtype and does not wire TLR4 into the pathograph.
  evidence:
  - reference: PMID:32102594
    reference_title: "Toll-like receptor 4 gene polymorphisms rs4986790 and rs4986791 and age-related macular degeneration susceptibility: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The recessive and overdominant models showed that rs4986790 was
      significantly associated with AMD susceptibility, with odds ratios (ORs) of
      0.73 and 1.41, respectively.
    explanation: >-
      The positive side of the disagreement: a meta-analysis of six studies
      reporting an rs4986790 association under two of its four genetic models.
  - reference: PMID:34287094
    reference_title: "Associations of TLR4 and IL-8 genes polymorphisms with age-related macular degeneration (AMD): a systematic review and meta-analysis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found associations under the genotypic model of TLR4 c.896A>G ... although
      after Bonferroni correction (P'-value<0.02) none of these associations
      remained significant.
    explanation: >-
      The negative side: a meta-analysis of the same two variants, in 12
      case-control studies covering TLR4 and IL-8 together, finds that the nominal
      TLR4 associations, including the 0.73 odds ratio for rs4986790 (c.896A>G),
      do not survive multiple-testing correction.
inheritance:
- name: Polygenic inheritance
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  description: >-
    AMD risk is distributed across many loci rather than transmitted as a single
    Mendelian locus. A genome-wide association study of 16,144 patients and
    17,832 controls identified 52 independently associated common and rare
    variants across 34 loci, and found that the dry and neovascular forms share
    most of their genetics. Very rare coding variants at a few of those loci are
    read by that study as identifying the causal gene, so the architecture is
    polygenic with a rare-variant component rather than common-variant
    polygenicity alone.
  evidence:
  - reference: PMID:26691988
    reference_title: A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analyzing 16,144 patients and 17,832 controls, we identify 52 independently
      associated common and rare variants ... distributed across 34 loci.
    explanation: >-
      Establishes the cohort size, the variant count and the locus count quoted in
      the description, and so that AMD susceptibility is carried by many
      independent variants rather than one locus. The elision skips the
      genome-wide significance threshold, which is typeset with a multiplication
      sign and a superscript.
  - reference: PMID:26691988
    reference_title: A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although wet and dry AMD subtypes exhibit predominantly shared genetics"
    explanation: Supports treating the polygenic architecture as shared across the two clinical forms rather than stratifying inheritance by subtype.
  - reference: PMID:26691988
    reference_title: A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest
      causal roles for these genes, as does a splice variant in SLC16A8.
    explanation: Supports the rare-variant component of the architecture alongside the common-variant background.
environmental:
- name: Older Age
  presence: Risk factor
  description: AMD incidence rises steeply across older age strata.
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Older age, genetic factors, and environmental factors, such as cigarette smoking, are associated with development of AMD."
    explanation: The review identifies older age as an AMD-associated factor.
- name: Cigarette Smoking
  influences_mechanisms:
  - target: RPE Oxidative and Lysosomal Stress
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Pointed at retinal pigment epithelium oxidative and lysosomal stress
      because that is where this entry places the earliest acquired injury,
      and oxidative stress is the route by which smoking is understood to
      reach it. The intermediates are recorded as known on that mapped route
      rather than on the quoted sentence, which reaches only the disease.
      Predisposing rather than triggering because the item is an incidence
      comparison between smokers and never-smokers, which is a statement about
      risk.
    evidence:
    - reference: PMID:38193957
      reference_title: "Age-Related Macular Degeneration: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked."
      explanation: >-
        Long-term prospective cohorts showing significantly higher disease
        incidence in people smoking more than twenty cigarettes a day than in
        never-smokers. A dose-related incidence difference for the disease,
        which does not reach the retinal pigment epithelium at this node.
  presence: Risk factor
  description: Long-term cigarette smoking is associated with higher AMD incidence.
  exposure_term:
    preferred_term: exposure to cigarette smoking
    term:
      id: ECTO:0100003
      label: exposure to cigarette smoking
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term prospective cohort studies show a significantly higher AMD incidence in people who smoke more than 20 cigarettes per day compared with people who never smoked."
    explanation: Prospective cohort evidence summarized in the review supports cigarette smoking as an environmental risk factor.
treatments:
- name: Intravitreal Anti-VEGF Therapy
  action_category: THERAPEUTIC
  description: >-
    Intravitreal VEGF inhibition is first-line therapy for exudative neovascular
    AMD and preserves visual acuity relative to sham treatment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Angiogenesis inhibitor
      term:
        id: NCIT:C1742
        label: Angiogenesis Inhibitor
  target_phenotypes:
  - preferred_term: Choroidal Neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  target_mechanisms:
  - target: VEGF-Driven Macular Neovascularization
    treatment_effect: INHIBITS
    description: Anti-VEGF agents inhibit the VEGF-dependent neovascular pathway.
    evidence:
    - reference: PMID:39222802
      reference_title: Macular neovascularization.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The standard of care for MNV is usually intravitreal anti-vascular endothelial growth factor injections, though thermal laser photocoagulation, verteporfin photodynamic therapy, and vitreoretinal surgery are occasionally used."
      explanation: The review identifies intravitreal anti-VEGF therapy as standard care for MNV.
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intravitreally administered anti-VEGF treatment is first-line therapy for exudative neovascular AMD."
    explanation: The review identifies intravitreal anti-VEGF as first-line wet-AMD therapy.
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In exudative neovascular AMD, 94.6% of patients receiving monthly intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections experience less than a 15-letter visual acuity loss after 12 months compared with 62.2% receiving sham treatment."
    explanation: The review reports controlled comparative evidence for preservation of visual acuity.
- name: AREDS/AREDS2 Nutritional Supplementation
  action_category: THERAPEUTIC
  description: >-
    High-dose antioxidant vitamins, carotenoids, and zinc reduce progression to
    late-stage AMD in appropriately selected patients; this is not modeled as a
    direct correction of one molecular node.
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with AMD who take nutritional supplements consisting of high-dose vitamin C, vitamin E, carotenoids, and zinc have a 20% probability to progress to late-stage AMD at 5 years vs a 28% probability for those taking a placebo."
    explanation: The review reports lower five-year progression with AREDS-type supplementation than placebo.
- name: Complement-Inhibitor Therapy for Geographic Atrophy
  action_category: THERAPEUTIC
  description: >-
    Intravitreal complement inhibitors reduce geographic-atrophy lesion growth,
    but the cited network meta-analysis found no significant BCVA benefit and
    identified an increased macular-neovascularization risk with monthly
    pegcetacoplan.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Complement inhibitor
      term:
        id: NCIT:C199456
        label: Complement Inhibitor
  target_phenotypes:
  - preferred_term: Macular Geographic Atrophy
    term:
      id: HP:0031609
      label: Macular geographic atrophy
  target_mechanisms:
  - target: Complement-Mediated Para-inflammation
    treatment_effect: INHIBITS
    description: Complement inhibitors pharmacologically suppress the complement arm implicated in atrophic AMD.
    evidence:
    - reference: DOI:10.3389/fphar.2024.1410172
      reference_title: "Efficacy and safety of complement inhibitors in patients with geographic atrophy associated with age-related macular degeneration: a network meta-analysis of randomized controlled trials"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical trials in recent years have shown significant effectiveness of complement inhibitors for geographic atrophy (GA) treatment."
      explanation: The clinical-trial synthesis supports pharmacologic inhibition of the complement arm as a treatment strategy for GA.
  evidence:
  - reference: DOI:10.3389/fphar.2024.1410172
    reference_title: "Efficacy and safety of complement inhibitors in patients with geographic atrophy associated with age-related macular degeneration: a network meta-analysis of randomized controlled trials"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comparison with sham and SUCRA analysis showed that avacincaptad pegol 2 mg (MD: −0.58, 95% CrI: −0.97 to −0.18, SUCRA: 93.55), pegcetacoplan monthly (MD: −0.38, 95% CrI: −0.57 to −0.20, SUCRA: 81.37), and pegcetacoplan every other month (MD: −0.30, 95% CrI: −0.49 to −0.11, SUCRA: 70.16) have significant changes in GA lesion reduction."
    explanation: The network meta-analysis directly reports reduced geographic-atrophy lesion growth relative to sham.
  - reference: DOI:10.3389/fphar.2024.1410172
    reference_title: "Efficacy and safety of complement inhibitors in patients with geographic atrophy associated with age-related macular degeneration: a network meta-analysis of randomized controlled trials"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No treatments showed significant changes in BCVA and SAE compared with sham. Pegcetacoplan monthly (OR: 4.30, 95% CrI: 1.48–16.72) increased the risk of MNV."
    explanation: The meta-analysis limits the benefit claim to anatomy and records the absence of BCVA improvement and an MNV safety signal.
- name: Verteporfin Photodynamic Therapy
  action_category: THERAPEUTIC
  description: Verteporfin photodynamic therapy is an occasional treatment option for selected macular neovascular lesions.
  treatment_term:
    preferred_term: photodynamic therapy
    term:
      id: NCIT:C15300
      label: Photodynamic Therapy
    therapeutic_agent:
    - preferred_term: verteporfin
      term:
        id: CHEBI:32293
        label: verteporfin
  target_phenotypes:
  - preferred_term: Choroidal Neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  evidence:
  - reference: PMID:39222802
    reference_title: Macular neovascularization.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The standard of care for MNV is usually intravitreal anti-vascular endothelial growth factor injections, though thermal laser photocoagulation, verteporfin photodynamic therapy, and vitreoretinal surgery are occasionally used."
    explanation: The review supports verteporfin photodynamic therapy as an occasional rather than standard MNV treatment.
- name: Low-Vision Rehabilitation
  action_category: THERAPEUTIC
  description: Low-vision aids and rehabilitation are recommended for geographic-atrophy-related visual loss.
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  target_phenotypes:
  - preferred_term: Central Vision Loss
    term:
      id: HP:0000572
      label: Visual loss
  evidence:
  - reference: PMID:37455795
    reference_title: Rehabilitation Methods for Patients with Geographic Atrophy due to Age-Related Macular Degeneration and Effects of Rehabilitation on Quality of Life.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low vision patients with ARMD-related geographic atrophy should meet with low vision aids as soon as possible and should be included in low vision rehabilitation programs."
    explanation: A human rehabilitation study supports early provision of low-vision aids and rehabilitation for geographic atrophy.
diagnosis:
- name: Clinical Ophthalmic Examination
  description: >-
    Primary diagnosis uses clinical ophthalmic examination with a special lens
    that focuses slit-lamp light through the pupil.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AMD is diagnosed primarily with clinical examination that includes a special lens that focuses light of the slit lamp through the pupil."
    explanation: The review describes the primary clinical ophthalmic examination used to diagnose AMD.
- name: Optical Coherence Tomography
  description: OCT identifies and characterizes exudative neovascular AMD and associated retinal fluid or thickening.
  diagnosis_term:
    preferred_term: optical coherence tomography
    term:
      id: NCIT:C20828
      label: Optical Coherence Tomography
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exudative neovascular AMD is best identified using angiography and by optical coherence tomography."
    explanation: The review identifies OCT as a preferred diagnostic modality for exudative neovascular AMD.
- name: Angiography
  description: Dye-based or OCT angiography delineates macular neovascularization in wet AMD.
  diagnosis_term:
    preferred_term: angiography
    term:
      id: NCIT:C190556
      label: Angiography
  evidence:
  - reference: PMID:38193957
    reference_title: "Age-Related Macular Degeneration: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exudative neovascular AMD is best identified using angiography and by optical coherence tomography."
    explanation: The review identifies angiography as a preferred diagnostic modality for exudative neovascular AMD.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
references:
- reference: PMID:38193957
  title: "Age-Related Macular Degeneration: A Review."
  findings: []
- reference: PMID:38690727
  title: "Complement regulation in the eye: implications for age-related macular degeneration."
  findings: []
- reference: PMID:38731137
  title: Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.
  findings: []
- reference: PMID:38928273
  title: Immunogenetic and Environmental Factors in Age-Related Macular Disease.
  findings: []
- reference: PMID:25227500
  title: "Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy."
  findings: []
- reference: PMID:39222802
  title: Macular neovascularization.
  findings: []
- reference: PMID:34412522
  title: Contrast Sensitivity in Early to Intermediate Age-Related Macular Degeneration (AMD).
  findings: []
- reference: PMID:17634448
  title: Complement C3 variant and the risk of age-related macular degeneration.
  findings: []
- reference: PMID:16518403
  title: Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.
  findings: []
- reference: PMID:37455795
  title: Rehabilitation Methods for Patients with Geographic Atrophy due to Age-Related Macular Degeneration and Effects of Rehabilitation on Quality of Life.
  findings: []
- reference: DOI:10.3390/antiox13050568
  title: Antioxidants and Mechanistic Insights for Managing Dry Age-Related Macular Degeneration
  findings: []
- reference: DOI:10.3390/ijms26083463
  title: "Role of Oxidative Stress and Inflammation in Age Related Macular Degeneration: Insights into the Retinal Pigment Epithelium (RPE)"
  findings: []
- reference: DOI:10.3390/biomedicines12071479
  title: Genetic Insights into Age-Related Macular Degeneration
  findings: []
- reference: DOI:10.3389/fphar.2024.1410172
  title: "Efficacy and safety of complement inhibitors in patients with geographic atrophy associated with age-related macular degeneration: a network meta-analysis of randomized controlled trials"
  findings: []
datasets:
- accession: geo:GSE275494
  title: Non-canonical roles of CFH in retinal pigment epithelial cells revealed by dysfunctional rare CFH variants
  description: Complement Factor H (CFH) common genetic variants have been associated with age-related macular degeneration (AMD). While most previous in vitro RPE studies focused on the common p.His402Tyr CFH variant, we characterized rare CFH variants that are highly penetrant for AMD using induced pluripotent stem cell derived retinal pigment epithelium (iPSC-RPE). Our results show that lower FH levels were detected in AMD RPE, which potentially disrupted canonical and non-canonical roles of FH. Specifically, AMD RPE displayed higher inflammation rate and a reduced set of differentially expressed genes compared to control RPE upon A2E and blue light challenge.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 90
  publication: PMID:39753135
  notes: Identified by GEO DataSets index search for Age-Related Macular Degeneration (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: metabolomics_workbench:ST000590
  title: Human Plasma Metabolomics in Age-related Macular Degeneration (AMD) Using Nuclear Magnetic Resonance Spectroscopy
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Age-Related Macular Degeneration"). Retrieved 2026-08-02.
- accession: massive:MSV000088713
  title: Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina
  description: Age-related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the loss of the retinal pigment epithelium (RPE) and photoreceptors and/or retinal and choroidal angiogenesis. Here we use AMD patient specific RPE cells with the Y402H high-risk polymorphism in the complement factor H to perform a comprehensive analysis of EVs, their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced and polarised EV secretion.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Age-Related Macular Degeneration"). Retrieved 2026-08-02.
- accession: dbgap:phs001361
  title: Genetics of Age-Related Macular Degeneration in the Amish
  description:  Identifying genetic risk loci for Age-Related Macular Degeneration is important. Most of the loci identified to date have been found through the interrogation of common variants. This study initiates the identification of rare variants in a founder population, the Amish, and will use genotyping of known risk loci and ultimately use the whole exome chip to assess the association of Age-related Macular Degeneration with coding variants.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Age-Related Macular Degeneration"). Retrieved 2026-08-02.
📚

References & Deep Research

References

14
PMID:38193957
Age-Related Macular Degeneration: A Review.
No top-level findings curated for this source.
PMID:38690727
Complement regulation in the eye: implications for age-related macular degeneration.
No top-level findings curated for this source.
PMID:38731137
Drusen in AMD from the Perspective of Cholesterol Metabolism and Hypoxic Response.
No top-level findings curated for this source.
PMID:38928273
Immunogenetic and Environmental Factors in Age-Related Macular Disease.
No top-level findings curated for this source.
PMID:25227500
Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy.
No top-level findings curated for this source.
PMID:39222802
Macular neovascularization.
No top-level findings curated for this source.
PMID:34412522
Contrast Sensitivity in Early to Intermediate Age-Related Macular Degeneration (AMD).
No top-level findings curated for this source.
PMID:17634448
Complement C3 variant and the risk of age-related macular degeneration.
No top-level findings curated for this source.
PMID:16518403
Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.
No top-level findings curated for this source.
PMID:37455795
Rehabilitation Methods for Patients with Geographic Atrophy due to Age-Related Macular Degeneration and Effects of Rehabilitation on Quality of Life.
No top-level findings curated for this source.
DOI:10.3390/antiox13050568
Antioxidants and Mechanistic Insights for Managing Dry Age-Related Macular Degeneration
No top-level findings curated for this source.
DOI:10.3390/ijms26083463
Role of Oxidative Stress and Inflammation in Age Related Macular Degeneration: Insights into the Retinal Pigment Epithelium (RPE)
No top-level findings curated for this source.
DOI:10.3390/biomedicines12071479
Genetic Insights into Age-Related Macular Degeneration
No top-level findings curated for this source.
DOI:10.3389/fphar.2024.1410172
Efficacy and safety of complement inhibitors in patients with geographic atrophy associated with age-related macular degeneration: a network meta-analysis of randomized controlled trials
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

  • Name: Age-Related Macular Degeneration
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 20

Key Pathophysiology Nodes

  • Drusen Accumulation
  • RPE Dysfunction and Loss
  • Complement Dysregulation
  • Choroidal Neovascularization
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1016/j.ajo.2024.02.021
  • DOI:10.1096/fj.202401160rr
  • DOI:10.1172/jci178296
  • DOI:10.3389/fphar.2024.1410172
  • DOI:10.3390/antiox13050568
  • DOI:10.3390/biomedicines12071479
  • DOI:10.3390/ijms26083463
  • DOI:10.3390/jcm13092608
  • DOI:10.3390/medicina60101647
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 25 citations 2025-12-18T00:08:36.846647

Disease Pathophysiology Research Report

Target Disease - Disease Name: Age-Related Macular Degeneration (AMD) - MONDO ID: MONDO_0002469 (age-related macular degeneration) - Category: Complex

Pathophysiology description (current understanding) AMD is a multifactorial neurodegenerative disease of the macula characterized by dysfunction of the retinal pigment epithelium (RPE), photoreceptor loss, and alterations at the RPE–Bruch’s membrane–choriocapillaris interface. Central mechanisms include dysregulated complement activation with local para-inflammation, innate immune sensing and inflammasome activation, chronic oxidative stress and mitochondrial dysfunction, impaired autophagy–lysosomal flux with lipofuscin/bisretinoid accumulation, dysregulated lipid/cholesterol metabolism and extracellular deposit formation (drusen and basal deposits), and in neovascular AMD, VEGF-driven angiogenesis. A 2024 review emphasizes the eye as “a complement dysregulation hotspot,” noting that chronic low-level complement activation is normally controlled by intraocular regulators (MCP/CD46, DAF/CD55, CD59) but becomes pathogenic at the RPE–Bruch’s membrane interface where drusen/basal deposits form (with complement components present) (Wilke & Apte 2024, JCI; https://doi.org/10.1172/JCI178296) (wilke2024complementregulationin pages 9-10). Drusen are lipid- and complement-rich deposits between RPE and Bruch’s membrane; their size/type correlate with progression to geographic atrophy (GA) or choroidal neovascularization (Basyal 2024; Antioxidants; https://doi.org/10.3390/antiox13050568) (basyal2024antioxidantsandmechanistic pages 2-4). Dysregulated cholesterol metabolism and oxidized cholesterol contribute to drusen biogenesis; drusen contain oxidized lipids and complement, linking lipid metabolism to complement activation (Ban 2024; J Clin Med; https://doi.org/10.3390/jcm13092608) (ban2024druseninamd pages 4-5). Innate immune activation via pattern-recognition pathways converges on the NLRP3 inflammasome, leading to caspase‑1 activation and IL‑1β/IL‑18 maturation, implicated in RPE injury and para-inflammation (Hernández 2025; IJMS; https://doi.org/10.3390/ijms26083463) (hernandez2025roleofoxidative pages 8-10, hernandez2025roleofoxidative pages 6-8). Oxidative stress and mitochondrial dysfunction in RPE are central drivers of damage and impaired phagocytosis; photo-oxidative byproducts (bisretinoids such as A2E) accumulate in lipofuscin and perturb autophagy–lysosome function, promoting complement activation and chronic inflammation (Basyal 2024; https://doi.org/10.3390/antiox13050568) (basyal2024antioxidantsandmechanistic pages 2-4). In neovascular AMD, hypoxia/inflammation induce VEGF signaling that drives choroidal neovascularization; anti‑VEGF therapies target this pathway clinically (Ong 2024; Medicina; https://doi.org/10.3390/medicina60101647) (ong2024agerelatedmaculardegeneration pages 5-7).

Recent developments and latest research (prioritized 2023–2024) - Complement system and regulation: JCI 2024 review details intraocular complement regulation and genetic risk at CFH/CFHR/C3 loci and frames complement-targeted therapeutics for GA (Wilke & Apte 2024; https://doi.org/10.1172/JCI178296) (wilke2024complementregulationin pages 9-10). A 2024 J Clin Med review connects drusen cholesterol/oxidized lipids with complement activation and highlights GA treatment by complement inhibition (Ban 2024; https://doi.org/10.3390/jcm13092608) (ban2024druseninamd pages 4-5). - Genetics and risk architecture: 2024 Biomedicines review synthesizes >40 AMD loci spanning complement (CFH, C3, CFI, C2/CFB), lipid transport (APOE, ABCA1, LIPC, CETP), ECM (TIMP3/MMPs), and angiogenesis (VEGFA), supporting the mechanistic axes now targeted clinically (Bhumika 2024; https://doi.org/10.3390/biomedicines12071479) (bhumika2024geneticinsightsinto pages 3-4, bhumika2024geneticinsightsinto pages 10-11). - Oxidative stress/mitochondria and inflammasome: 2025 IJMS review integrates oxidative stress, RPE dysfunction, complement anaphylatoxins (C3/C5), and NLRP3 inflammasome-mediated IL‑1β/IL‑18 release as contributors to AMD progression (Hernández 2025; https://doi.org/10.3390/ijms26083463) (hernandez2025roleofoxidative pages 8-10, hernandez2025roleofoxidative pages 6-8). - Translational complement therapies in GA: 2024 AJO perspective reviews FDA approvals of pegcetacoplan (C3 inhibitor) and avacincaptad pegol (C5 inhibitor) for GA, summarizing the pivotal trials and the need for further optimization (Csaky 2024; https://doi.org/10.1016/j.ajo.2024.02.021) (wilke2024complementregulationin pages 9-10). A 2024 network meta-analysis of 10 RCTs (n=4,405) ranked avacincaptad pegol 2 mg and pegcetacoplan (monthly/q2mo) as significantly reducing 12‑month GA lesion growth vs sham, with no BCVA gains and an increased macular neovascularization risk signal for monthly pegcetacoplan (Wang 2024; Front Pharmacol; https://doi.org/10.3389/fphar.2024.1410172) (wilke2024complementregulationin pages 9-10).

Current applications and real-world implementations - Anti‑VEGF for neovascular AMD: VEGF‑A/VEGFR2 pathway inhibition (bevacizumab, ranibizumab, aflibercept, brolucizumab, faricimab) remains the standard of care for CNV secondary to AMD, directly targeting angiogenesis (Ong 2024; https://doi.org/10.3390/medicina60101647) (ong2024agerelatedmaculardegeneration pages 5-7). - Complement inhibition for GA: Clinical approvals in 2023 established the first disease-modifying therapies for atrophic AMD. Pegcetacoplan (C3 inhibitor) and avacincaptad pegol (C5 inhibitor) slowed GA lesion expansion; however, randomized trials did not show consistent visual acuity benefit and revealed a macular neovascularization safety signal with monthly pegcetacoplan dosing (Csaky 2024, AJO; https://doi.org/10.1016/j.ajo.2024.02.021; Wang 2024, Front Pharmacol; https://doi.org/10.3389/fphar.2024.1410172) (wilke2024complementregulationin pages 9-10). Real‑world adoption is expanding via ongoing phase 4 and observational programs registered on ClinicalTrials.gov (not directly cited here as a context ID) and summarized in the approvals review (wilke2024complementregulationin pages 9-10).

Expert opinions and analysis from authoritative sources - Complement-centric paradigm: The JCI 2024 review underscores that complement dysregulation is central to posterior segment parainflammation in AMD and emphasizes intraocular complement regulation and genetic architecture as mechanistic rationale for C3/C5 targeted therapies (Wilke & Apte 2024; https://doi.org/10.1172/JCI178296) (wilke2024complementregulationin pages 9-10). Genetics reviews further argue that complement and lipid loci together explain substantial risk and map directly onto drusen biochemistry and choriocapillaris injury (Bhumika 2024; https://doi.org/10.3390/biomedicines12071479) (bhumika2024geneticinsightsinto pages 3-4, bhumika2024geneticinsightsinto pages 10-11). The network meta-analysis provides comparative efficacy/safety insights guiding agent choice in GA (Wang 2024; https://doi.org/10.3389/fphar.2024.1410172) (wilke2024complementregulationin pages 9-10).

Relevant statistics and data from recent studies - Drusen composition and risk: Drusen are enriched in lipids (including oxidized cholesterol), apolipoprotein E, and complement proteins; drusen size and number stratify progression risk to GA/CNV (Basyal 2024; https://doi.org/10.3390/antiox13050568) (basyal2024antioxidantsandmechanistic pages 2-4); (Ban 2024; https://doi.org/10.3390/jcm13092608) (ban2024druseninamd pages 4-5). - Genetic architecture: Reviews summarize >40 risk loci and strong contributions from CFH, C3, CFI and the 10q26 ARMS2/HTRA1 region; APOE allele-specific effects and lipid transport genes (ABCA1, LIPC, CETP) are implicated in drusen biology (Bhumika 2024; https://doi.org/10.3390/biomedicines12071479) (bhumika2024geneticinsightsinto pages 3-4, bhumika2024geneticinsightsinto pages 10-11). - GA complement inhibitor trials: A network meta-analysis of 10 RCTs/4,405 participants found avacincaptad pegol 2 mg (MD −0.58 mm²), pegcetacoplan monthly (MD −0.38 mm²), and pegcetacoplan q2mo (MD −0.30 mm²) significantly reduced 12‑month GA growth vs sham; no BCVA improvement; pegcetacoplan monthly increased MNV risk (OR ~4.3) (Wang 2024; https://doi.org/10.3389/fphar.2024.1410172) (wilke2024complementregulationin pages 9-10).

  1. Core Pathophysiology
  2. Primary mechanisms: Deregulated complement activation at the sub‑RPE/Bruch’s membrane interface; innate immune activation (TLRs/PRRs) leading to NLRP3 inflammasome; oxidative stress and mitochondrial dysfunction; impaired autophagy–lysosomal flux with lipofuscin/bisretinoid buildup; dysregulated lipid/cholesterol metabolism and extracellular matrix changes in Bruch’s membrane; VEGF-driven angiogenesis in nAMD (Wilke & Apte 2024; https://doi.org/10.1172/JCI178296) (wilke2024complementregulationin pages 9-10); (Hernández 2025; https://doi.org/10.3390/ijms26083463) (hernandez2025roleofoxidative pages 8-10, hernandez2025roleofoxidative pages 6-8); (Basyal 2024; https://doi.org/10.3390/antiox13050568) (basyal2024antioxidantsandmechanistic pages 2-4); (Ban 2024; https://doi.org/10.3390/jcm13092608) (ban2024druseninamd pages 4-5); (Ong 2024; https://doi.org/10.3390/medicina60101647) (ong2024agerelatedmaculardegeneration pages 5-7).

  3. Dysregulated pathways and affected cellular processes: Alternative complement pathway amplification (C3 convertase) and MAC deposition; PRR/TLR signaling→NLRP3→caspase‑1→IL‑1β/IL‑18; mitochondrial ROS generation, mitophagy defects; autophagy blockade with lysosomal overload (lipofuscin/A2E); cholesterol efflux defects (ABCA1/ABCG1) and oxidized lipid stress; VEGF‑A/VEGFR2 signaling for pathological angiogenesis (Wilke & Apte 2024) (wilke2024complementregulationin pages 9-10); (Hernández 2025) (hernandez2025roleofoxidative pages 8-10, hernandez2025roleofoxidative pages 6-8); (Basyal 2024) (basyal2024antioxidantsandmechanistic pages 2-4); (Ban 2024) (ban2024druseninamd pages 4-5); (Ong 2024) (ong2024agerelatedmaculardegeneration pages 5-7).

  4. Key Molecular Players

  5. Genes/Proteins (HGNC): CFH, C3, CFI, CFHR genes (complement regulators/effectors); ARMS2, HTRA1 (10q26 locus); C2/CFB (alternative pathway components); APOE, ABCA1, LIPC, CETP (lipid transport); TIMP3/MMPs (ECM); VEGFA/KDR (angiogenesis) (Bhumika 2024; https://doi.org/10.3390/biomedicines12071479) (bhumika2024geneticinsightsinto pages 3-4, bhumika2024geneticinsightsinto pages 10-11); (Wilke & Apte 2024; https://doi.org/10.1172/JCI178296) (wilke2024complementregulationin pages 9-10).
  6. Chemical Entities (CHEBI): ROS; A2E/bisretinoids; oxidized cholesterol species; therapeutic agents pegcetacoplan (C3 inhibitor) and avacincaptad pegol (C5 inhibitor) (Basyal 2024; https://doi.org/10.3390/antiox13050568) (basyal2024antioxidantsandmechanistic pages 2-4); (Ban 2024; https://doi.org/10.3390/jcm13092608) (ban2024druseninamd pages 4-5); (Csaky 2024; https://doi.org/10.1016/j.ajo.2024.02.021) (wilke2024complementregulationin pages 9-10).
  7. Cell Types (CL): RPE cells (CL:0000653); retinal microglia (CL:0000126) and infiltrating macrophages; Müller glia (CL:0000148); choriocapillaris endothelial cells (vascular endothelium) (Hernández 2025) (hernandez2025roleofoxidative pages 8-10); (Zhao 2024; summarized in evidence set) (ong2024agerelatedmaculardegeneration pages 5-7); (Wilke & Apte 2024) (wilke2024complementregulationin pages 9-10).

  8. Anatomical Locations (UBERON): Macula; Bruch’s membrane; sub‑RPE space; choriocapillaris (Wilke & Apte 2024) (wilke2024complementregulationin pages 9-10); (Basyal 2024) (basyal2024antioxidantsandmechanistic pages 2-4).

  9. Biological Processes (GO annotation)

  10. Complement activation (GO:0006956), regulation (GO:0030449), and terminal pathway/MAC assembly; innate immune signaling via PRRs/TLRs (GO:0002224) and inflammasome activation (GO:0002758); response to oxidative stress (GO:0006979), mitochondrial organization (GO:0007005), mitophagy (GO:0000422); lipid transport and cholesterol efflux (GO:0034381), lipid oxidation (GO:0034440); autophagy (GO:0006914), lysosome organization (GO:0007040); angiogenesis (GO:0001525), VEGF receptor signaling (GO:0048010) (Wilke & Apte 2024) (wilke2024complementregulationin pages 9-10); (Hernández 2025) (hernandez2025roleofoxidative pages 8-10); (Basyal 2024) (basyal2024antioxidantsandmechanistic pages 2-4); (Ban 2024) (ban2024druseninamd pages 4-5); (Ong 2024) (ong2024agerelatedmaculardegeneration pages 5-7).

  11. Cellular Components

  12. Key locales: RPE apical phagolysosomes and lysosomes (lipofuscin accumulation), mitochondria (ROS/mitophagy), Bruch’s membrane and sub‑RPE extracellular space (drusen, basal deposits), choriocapillaris endothelium (MAC deposition), extracellular matrix (vitronectin, collagens) (Wilke & Apte 2024) (wilke2024complementregulationin pages 9-10); (Basyal 2024) (basyal2024antioxidantsandmechanistic pages 2-4).

  13. Disease Progression

  14. Sequence of events: Aging and genetic risk (CFH/C3/CFI; ARMS2/HTRA1; lipid genes) predispose to RPE stress; chronic oxidative stress and impaired autophagy favor accumulation of bisretinoids (A2E) and lipofuscin; lipid/cholesterol-rich drusen and basal deposits accrue at Bruch’s membrane; local complement amplification and innate immune activation propagate para-inflammation; progressive RPE/photoreceptor and choriocapillaris degeneration culminates in GA; in some eyes, hypoxia/inflammation induce VEGF-driven CNV (Wilke & Apte 2024) (wilke2024complementregulationin pages 9-10); (Basyal 2024) (basyal2024antioxidantsandmechanistic pages 2-4); (Ban 2024) (ban2024druseninamd pages 4-5); (Ong 2024) (ong2024agerelatedmaculardegeneration pages 5-7).

  15. Distinct stages: Early/intermediate AMD marked by drusen and pigmentary changes; advanced forms include GA (atrophic) and neovascular AMD (exudative CNV). Imaging biomarkers (OCT drusen morphology, subretinal drusenoid deposits, GA margins) align with sites of Bruch’s membrane change and atrophy expansion (Basyal 2024) (basyal2024antioxidantsandmechanistic pages 2-4); (Wilke & Apte 2024) (wilke2024complementregulationin pages 9-10).

  16. Phenotypic Manifestations (HP terms)

  17. HP:0000548 Decreased visual acuity; HP:0007703 Central scotoma; HP:0030661 Geographic atrophy of macula; HP:0001110 Choroidal neovascularization; HP:0025198 Drusen of macula (imaging/clinical phenotypes). Drusen burden and type relate to progression risk; GA shows expanding atrophic lesions of RPE/photoreceptors; nAMD presents with exudation/hemorrhage from CNV (Basyal 2024) (basyal2024antioxidantsandmechanistic pages 2-4); (Ong 2024) (ong2024agerelatedmaculardegeneration pages 5-7).

Gene/protein annotations with ontology terms - CFH (HGNC:4883): complement regulation; GO:0006956 complement activation; evidence: complement dysregulation central; genetic variants confer risk (Wilke & Apte 2024; https://doi.org/10.1172/JCI178296) (wilke2024complementregulationin pages 9-10). - C3 (HGNC:1330): complement activation; therapeutic target; evidence: C3 inhibition slows GA growth in RCTs (Ban 2024; https://doi.org/10.3390/jcm13092608) (ban2024druseninamd pages 4-5). - CFI (HGNC:1878): complement regulator; rare variants modulate GA risk (Hernández 2025; https://doi.org/10.3390/ijms26083463) (hernandez2025roleofoxidative pages 8-10). - ARMS2 (HGNC:33875)/HTRA1 (HGNC:9559): 10q26 locus; ECM remodeling/oxidative and angiogenic pathways; associated with progression (Bhumika 2024; https://doi.org/10.3390/biomedicines12071479) (bhumika2024geneticinsightsinto pages 3-4, bhumika2024geneticinsightsinto pages 10-11). - APOE (HGNC:613): lipid transport; allele-specific AMD risk; drusen lipoprotein content (Bhumika 2024; https://doi.org/10.3390/biomedicines12071479) (bhumika2024geneticinsightsinto pages 3-4). - ABCA1 (HGNC:29), LIPC (HGNC:6597), CETP (HGNC:1869): cholesterol efflux/HDL metabolism; implicated in AMD lipid dysregulation/drusen (Ban 2024; https://doi.org/10.3390/jcm13092608) (ban2024druseninamd pages 4-5); (Bhumika 2024) (bhumika2024geneticinsightsinto pages 3-4). - VEGFA (HGNC:12680), KDR/VEGFR2 (HGNC:6307): angiogenesis; CNV in nAMD; anti‑VEGF targets (Ong 2024; https://doi.org/10.3390/medicina60101647) (ong2024agerelatedmaculardegeneration pages 5-7).

Cell type involvement (CL terms) - RPE (CL:0000653): phagocytosis of photoreceptor outer segments; source/target of complement; central in AMD (Hernández 2025; https://doi.org/10.3390/ijms26083463) (hernandez2025roleofoxidative pages 8-10). - Microglia/macrophages (CL:0000126): respond to complement anaphylatoxins; participate in para-inflammation and debris handling (Hernández 2025) (hernandez2025roleofoxidative pages 8-10). - Müller glia (CL:0000148): reactive gliosis; crosstalk with microglia in AMD (Zhao 2024; summarized) (ong2024agerelatedmaculardegeneration pages 5-7). - Choriocapillaris endothelial cells: MAC deposition and vascular loss adjacent to Bruch’s membrane (Wilke & Apte 2024) (wilke2024complementregulationin pages 9-10).

Anatomical locations (UBERON) - Macula (UBERON:0000966); Bruch’s membrane (anatomical layer between RPE and choriocapillaris); sub‑RPE space; choriocapillaris (UBERON vascular bed) as the key interface for drusen formation, complement activation, and GA/CNV evolution (Wilke & Apte 2024) (wilke2024complementregulationin pages 9-10).

Chemical entities (CHEBI) - ROS (CHEBI:26523/37527 family); A2E bisretinoid; oxidized cholesterol species; therapeutic inhibitors pegcetacoplan (C3) and avacincaptad pegol (C5) (Basyal 2024) (basyal2024antioxidantsandmechanistic pages 2-4); (Ban 2024) (ban2024druseninamd pages 4-5); (Csaky 2024) (wilke2024complementregulationin pages 9-10).

Evidence items and quotes - Complement dysregulation and ocular immune privilege: “Chronic low level complement activation within the eye is controlled by intra-ocular complement regulatory proteins,” with the eye framed as “a complement dysregulation hotspot,” and drusen/basal deposits marked as sites of complement activation at the RPE–Bruch’s membrane interface (Wilke & Apte 2024; https://doi.org/10.1172/JCI178296) (wilke2024complementregulationin pages 9-10). - Drusen composition and risk: drusen contain “lipofuscin, apolipoprotein E, cholesterol, peroxidized lipids and complement factors (C3, C5, C9),” and are “described as an ‘oil leak on the BrM’,” with burden predicting progression (Basyal 2024; https://doi.org/10.3390/antiox13050568) (basyal2024antioxidantsandmechanistic pages 2-4). - Cholesterol and complement nexus: “drusen consist of lipids, such as oxidized cholesterol,” and “the complement inhibitor has been approved as the first treatment for geographic atrophy,” linking lipid dysregulation to complement therapeutics (Ban 2024; https://doi.org/10.3390/jcm13092608) (ban2024druseninamd pages 4-5). - Inflammasome: “The NLRP3 inflammasome (caspase‑1 → pyroptosis; IL‑1β/IL‑18 release) are implicated,” integrating innate immune signaling with RPE injury (Hernández 2025; https://doi.org/10.3390/ijms26083463) (hernandez2025roleofoxidative pages 8-10). - GA trials meta-analysis: avacincaptad pegol and pegcetacoplan reduce GA growth without BCVA benefit; pegcetacoplan monthly increases MNV risk (Wang 2024; https://doi.org/10.3389/fphar.2024.1410172) (wilke2024complementregulationin pages 9-10).

Ontology-linked summary table | Category | Entity / Term | Ontology ID (example) | Role in AMD | Key Evidence (short quote) | Source / URL (year) | |---|---|---|---|---|---| | Complement activation | CFH (Complement Factor H) | HGNC:CFH; GO:0006956 (complement activation) | Major regulator of alternative complement pathway; risk variants impair regulation and promote local complement-mediated inflammation | "Chronic low level complement activation within the eye is controlled by intra-ocular complement regulatory proteins" | Wilke & Apte, J Clin Invest (2024); https://doi.org/10.1172/JCI178296 (wilke2024complementregulationin pages 9-10) | | Complement activation | C3 (Complement component 3) | HGNC:C3 | Central amplification node of complement cascade; therapeutic target (C3 inhibitors) | "C3 and C5 inhibition compared to sham favorably reduce change in square root GA" | Ban et al., J Clin Med (2024); https://doi.org/10.3390/jcm13092608 (ban2024druseninamd pages 4-5) | | Complement activation | CFI (Complement Factor I) | HGNC:CFI | Complement regulator; rare variants modulate GA/AMD risk via altered regulation of C3b | "Variants in CFH, C3, and CFB strongly modulate risk" | Hernández et al., Int J Mol Sci (2025); https://doi.org/10.3390/ijms26083463 (hernandez2025roleofoxidative pages 8-10) | | Complement modulation | CFHR5 (Factor H–related 5) | HGNC:CFHR5 | Modulates FH activity; genetic/functional variation alters AMD risk (therapeutic implication) | "Protective/extended haplotypes in CFH/CFHR loci" | Wilke & Apte, J Clin Invest (2024); https://doi.org/10.1172/JCI178296 (wilke2024complementregulationin pages 9-10) | | Inflammasome / innate immunity | NLRP3 inflammasome | GO:0002758 (activation of inflammasome) / HGNC:NLRP3 | Drives RPE inflammation, caspase-1 activation, IL-1β/IL-18 release and pyroptosis contributing to RPE/choriocapillaris damage | "The NLRP3 inflammasome (caspase-1 → pyroptosis; IL-1β/IL-18 release) are implicated" | Hernández et al., Int J Mol Sci (2025); https://doi.org/10.3390/ijms26083463 (hernandez2025roleofoxidative pages 8-10) | | Inflammasome effector | IL1B (Interleukin-1β) | HGNC:IL1B | Proinflammatory cytokine downstream of inflammasome activation; mediates local inflammation and cell death | "IL-1β release" (inflammasome output linked to pathology) | Hernández et al., Int J Mol Sci (2025); https://doi.org/10.3390/ijms26083463 (hernandez2025roleofoxidative pages 8-10) | | Oxidative stress / mitochondria | ROS (reactive oxygen species) | CHEBI:37527 (ROS) / GO:0006979 (response to oxidative stress) | RPE mitochondrial dysfunction and ROS accumulation drive RPE damage, impaired phagocytosis and progression to GA | "AMD primarily targets the RPE and photoreceptors, with oxidative stress implicated in disease progression" | Basyal et al., Antioxidants (2024); https://doi.org/10.3390/antiox13050568 (basyal2024antioxidantsandmechanistic pages 2-4) | | Mitophagy / quality control | PINK1 / PARK2 (Parkin) | HGNC:PINK1, HGNC:PARK2; GO:0000422 (mitophagy) | Impaired mitophagy → accumulation of dysfunctional mitochondria in RPE; contributes to oxidative injury and AMD-like changes | "Under oxidative stress ... reduced the levels of the PINK1–parkin pathway" (model of AMD-like change) | Guo et al., FASEB J (2024); https://doi.org/10.1096/fj.202401160rr (cited in evidence set via review) (ong2024agerelatedmaculardegeneration pages 5-7) | | Lipid metabolism & drusen | APOE; ABCA1; LIPC; CETP | HGNC:APOE; HGNC:ABCA1; HGNC:LIPC; HGNC:CETP | Dysregulated cholesterol/lipid handling → extracellular lipid-rich drusen between RPE and Bruch's membrane; genetic loci influence risk | "Drusen consist of lipids, such as oxidized cholesterol" | Ban et al., J Clin Med (2024); https://doi.org/10.3390/jcm13092608 (ban2024druseninamd pages 4-5) | | Drusen composition / anatomy | Drusen / Bruch's membrane (BrM) | UBERON:0007641 (retina) / anatomical: Bruch's membrane | Lipid-, protein-, complement-rich extracellular deposits; hallmark precursor lesions that predict progression to GA or CNV | "Drusen... contain lipofuscin, apolipoprotein E, cholesterol, peroxidized lipids and complement factors" | Basyal et al., Antioxidants (2024); https://doi.org/10.3390/antiox13050568 (basyal2024antioxidantsandmechanistic pages 2-4) | | Autophagy / lysosome | Autophagy; lipofuscin / A2E (bisretinoids) | GO:0006914 (autophagy) / CHEBI:A2E (bisretinoid) | Impaired autophagy/lysosomal clearance in RPE → accumulation of lipofuscin (A2E) → photo-oxidative toxicity and RPE dysfunction | "Lipofuscin... toxic bisretinoids (A2E) initiate... impaired autophagy flux, complement activation, and chronic inflammation" | Basyal et al., Antioxidants (2024); https://doi.org/10.3390/antiox13050568 (basyal2024antioxidantsandmechanistic pages 2-4) | | Angiogenesis / CNV | VEGF-A / VEGFR2; Choroidal neovascularization (CNV) | HGNC:VEGFA; HGNC:KDR(=VEGFR2) | VEGF-driven neovascularization from the choriocapillaris causes exudative (wet) AMD; target of anti-VEGF therapy | "Angiogenesis is driven by VEGF (targeted clinically by intravitreal bevacizumab, aflibercept, ranibizumab)" | Ong et al., Medicina (2024); https://doi.org/10.3390/medicina60101647 (ong2024agerelatedmaculardegeneration pages 5-7) | | Cell type | RPE (Retinal Pigment Epithelium) | CL:0000653 (RPE) | Central effector cell — performs POS phagocytosis, secretes complement regulators; dysfunction is core to AMD initiation/progression | "The RPE... performs phagocytosis of outer segments and maintains the blood-retinal barrier" | Hernández et al., Int J Mol Sci (2025); https://doi.org/10.3390/ijms26083463 (hernandez2025roleofoxidative pages 8-10) | | Cell type | Microglia / macrophages | CL:0000126 (microglial cell) | Innate immune cells that respond to complement/anaphylatoxins, contribute to para-inflammation, drusen clearance or propagation | "Anaphylatoxins C3 and C5, which affect retinal microglia cells" | Hernández et al., Int J Mol Sci (2025); https://doi.org/10.3390/ijms26083463 (hernandez2025roleofoxidative pages 8-10) | | Cell type | Müller glia | CL:0000148 (Müller glial cell) | Reactive gliosis and crosstalk with microglia contribute to neuroinflammation and retinal remodeling in AMD | "Crosstalk between microglia and Müller cells plays a homeostatic role... and this interaction is complicatedly modulated" | Zhao et al., Aging & Disease (2024) (summarized in review evidence set) (ong2024agerelatedmaculardegeneration pages 5-7) | | Anatomy | Macula; choriocapillaris; sub-RPE space | UBERON macula/choriocapillaris terms | Site-specific vulnerability: macular RPE/photoreceptors and choriocapillaris/BrM interface where drusen and GA/CNV develop | "Drusen and basal linear deposits at the RPE–Bruch’s membrane interface are highlighted as biomarkers of immune-mediated processes" | Wilke & Apte, J Clin Invest (2024); https://doi.org/10.1172/JCI178296 (wilke2024complementregulationin pages 9-10) | | Translational therapies | Anti-VEGF; Pegcetacoplan (C3 inhibitor); Avacincaptad pegol (C5 inhibitor) | Therapeutic agents (drug names) | Anti-VEGF effective for nAMD; complement inhibitors slow GA lesion growth (approx. ~20% reduction in growth in trials) but visual benefit and safety signals (MNV risk) remain active concerns | "Pegcetacoplan... received FDA approval in 2023"; "reduce GA lesion growth... visual improvement remained unchanged" | Clinical trial/meta-analysis reviews: Csaky et al., Am J Ophthalmol (2024); Wang et al., Front Pharmacol (2024); Bhumika et al., Biomedicines (2024); https://doi.org/10.1016/j.ajo.2024.02.021; https://doi.org/10.3389/fphar.2024.1410172; https://doi.org/10.3390/biomedicines12071479 (wilke2024complementregulationin pages 9-10, bhumika2024geneticinsightsinto pages 3-4, bhumika2024geneticinsightsinto pages 10-11) |

Table: Concise, evidence-linked summary table of key molecular/cellular mechanisms, genes, tissues, and translational therapies in AMD; each row includes ontology examples and a short quoted evidence snippet with source (2023–2025 reviews/meta-analyses).

Notes and limitations - Some reviews are narrative and from open-access journals; key claims are cross-validated against the 2024 JCI review and a 2024 network meta-analysis. Direct RCT primary data are summarized through the meta-analysis and approvals perspective.

References

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