Hypermobile Ehlers-Danlos Syndrome <-> Panic Disorder

Comorbidity A_BEFORE_B CANDIDATE

Panic disorder/agoraphobia is the single anxiety disorder most consistently and specifically associated with joint hypermobility across a body of case-control and cohort literature spanning three decades, largely from one research group (Bulbena, Martín-Santos and colleagues, Barcelona). A 1993 case-control study found panic disorder, agoraphobia, and simple phobia -- but not generalized anxiety disorder, dysthymic disorder, or major depression -- were specifically elevated in joint hypermobility syndrome (age- and sex-adjusted OR 10.7). A 1998 case-control study replicated this in patients newly diagnosed with panic disorder/agoraphobia (67.7% had joint hypermobility syndrome versus 10.1%-12.5% of controls). A 2010 case-control study replicated the association against three separate control groups (psychiatric, fibromyalgia, and healthy). A 2011 prospective 15-year cohort study established temporal precedence: joint hypermobility syndrome assessed at baseline (ages 16-20) predicted a markedly higher cumulative incidence of panic/agoraphobia at follow-up (relative risk 22.3). A 2012 systematic review of 17 studies concluded panic disorder/agoraphobia was the anxiety disorder most consistently linked to joint hypermobility across the literature. These studies predate the 2017 hEDS diagnostic criteria and use Beighton-criteria "joint hypermobility syndrome" (JHS), the diagnostic predecessor that was folded into the hypermobility spectrum disorder/hEDS nosology; they are treated here as the closest available literature for the current hEDS diagnosis. Directionality is recorded as A_BEFORE_B on the strength of the 2011 prospective cohort, in contrast to most other hEDS comorbidity entries in this KB where only cross-sectional evidence exists. No ICEES KG signal exists for this pair: hEDS (MONDO:0007523) is not a node in the ICEES KG snapshot at all (confirmed while curating the hEDS-POTS comorbidity entry).

Disease A

Hypermobile Ehlers-Danlos Syndrome

Slug:Hypermobile_Ehlers-Danlos_Syndrome

Disease B

Panic Disorder

Slug:Panic_Disorder

Causal Mechanism Graphs

Hypermobile Ehlers-Danlos Syndrome

graph LR
    Sleep_disturbance["Sleep disturbance"]
    Joint_instability_and_recurrent_soft_tissue_injury["Joint instability and recurrent soft-tissue injury"]
    Candidate_extracellular_matrix_remodeling_abnormalities["Candidate extracellular matrix remodeling abnormalities"]
    Myofibroblast_like_fibroblast_transition["Myofibroblast-like fibroblast transition"]
    Chronic_pain["Chronic pain"]
    Arthralgia["Arthralgia"]
    Joint_dislocation["Joint dislocation"]
    Joint_hypermobility["Joint hypermobility"]

    Candidate_extracellular_matrix_remodeling_abnormalities --> Myofibroblast_like_fibroblast_transition
    Joint_instability_and_recurrent_soft_tissue_injury --> Joint_dislocation
    Joint_instability_and_recurrent_soft_tissue_injury --> Chronic_pain
    Joint_instability_and_recurrent_soft_tissue_injury --> Arthralgia
    Joint_hypermobility --> Joint_instability_and_recurrent_soft_tissue_injury
    Chronic_pain --> Sleep_disturbance

    style Sleep_disturbance fill:#fef3c7
    style Joint_instability_and_recurrent_soft_tissue_injury fill:#dbeafe
    style Candidate_extracellular_matrix_remodeling_abnormalities fill:#dbeafe
    style Myofibroblast_like_fibroblast_transition fill:#dbeafe
    style Chronic_pain fill:#fef3c7
    style Arthralgia fill:#fef3c7
    style Joint_dislocation fill:#fef3c7
    style Joint_hypermobility fill:#fef3c7

Panic Disorder

graph LR
    GABAergic_and_Serotonergic_Amygdala_Signaling["GABAergic and Serotonergic Amygdala Signaling"]
    SSRI_and_SNRI_pharmacotherapy["SSRI and SNRI pharmacotherapy"]
    Cognitive_behavioral_therapy["Cognitive behavioral therapy"]
    Anxiety["Anxiety"]
    Childhood_Adversity_Risk["Childhood Adversity Risk"]
    Benzodiazepine_pharmacotherapy["Benzodiazepine pharmacotherapy"]
    Fear_and_Interoceptive_Circuit_Dysregulation["Fear and Interoceptive Circuit Dysregulation"]
    Episodic_Paroxysmal_Anxiety["Episodic Paroxysmal Anxiety"]
    Orexin_and_Hypothalamic_Panic_Reactivity["Orexin and Hypothalamic Panic Reactivity"]

    Childhood_Adversity_Risk --> Fear_and_Interoceptive_Circuit_Dysregulation
    Fear_and_Interoceptive_Circuit_Dysregulation --> Episodic_Paroxysmal_Anxiety
    GABAergic_and_Serotonergic_Amygdala_Signaling --> Fear_and_Interoceptive_Circuit_Dysregulation
    Orexin_and_Hypothalamic_Panic_Reactivity --> Episodic_Paroxysmal_Anxiety
    Cognitive_behavioral_therapy --> Episodic_Paroxysmal_Anxiety
    Cognitive_behavioral_therapy --> Anxiety
    SSRI_and_SNRI_pharmacotherapy --> GABAergic_and_Serotonergic_Amygdala_Signaling
    SSRI_and_SNRI_pharmacotherapy --> Episodic_Paroxysmal_Anxiety
    SSRI_and_SNRI_pharmacotherapy --> Anxiety
    Benzodiazepine_pharmacotherapy --> GABAergic_and_Serotonergic_Amygdala_Signaling
    Benzodiazepine_pharmacotherapy --> Episodic_Paroxysmal_Anxiety
    Benzodiazepine_pharmacotherapy --> Anxiety

    style GABAergic_and_Serotonergic_Amygdala_Signaling fill:#dbeafe
    style SSRI_and_SNRI_pharmacotherapy fill:#fce7f3
    style Cognitive_behavioral_therapy fill:#fce7f3
    style Anxiety fill:#fef3c7
    style Childhood_Adversity_Risk fill:#dbeafe
    style Benzodiazepine_pharmacotherapy fill:#fce7f3
    style Fear_and_Interoceptive_Circuit_Dysregulation fill:#dbeafe
    style Episodic_Paroxysmal_Anxiety fill:#fef3c7
    style Orexin_and_Hypothalamic_Panic_Reactivity fill:#dbeafe

Association Signals

Signal 1

Population:Case-control study, 114 cases of joint hypermobility syndrome diagnosed at a rheumatology outpatient clinic (Hospital del Mar, Barcelona) versus 59 controls from the same clinic.

Signal IDs: MONDO:0007523 dismech -> MONDO:0005383 dismech

Temporal: A before B: , B before A: , Same time:

AOR: 10.7

CI: -

FDR:

Age- and sex-adjusted odds ratio for panic disorder, agoraphobia, and simple phobia in JHS versus controls, as reported by the source. Generalized anxiety disorder, dysthymic disorder, and major depression were explicitly not associated.

PMID:8464956 (SUPPORT)

Source: HUMAN_CLINICAL

"DSM-III-R diagnoses of panic disorder, agoraphobia, and simple phobia, but not generalized anxiety disorder, dysthymic disorder, or major depression were found to be highly associated with JHS (age- and sex-adjusted odds ratio = 10.7)."

Directly quantifies the panic/phobic-specific association and its adjusted odds ratio.

Signal 2

Population:Case-control study, 99 newly diagnosed, untreated patients with panic disorder, agoraphobia, or both versus 99 psychiatric controls and 64 medical controls (Spain).

Signal IDs: MONDO:0007523 dismech -> MONDO:0005383 dismech

Temporal: A before B: , B before A: , Same time:

PREVALENCE: 67.7

CI: -

FDR:

Prevalence of joint hypermobility syndrome in the panic disorder/agoraphobia group.

PREVALENCE: 10.1

CI: -

FDR:

Prevalence of joint hypermobility syndrome in the psychiatric control group.

PREVALENCE: 12.5

CI: -

FDR:

Prevalence of joint hypermobility syndrome in the medical control group.

PMID:9812121 (SUPPORT)

Source: HUMAN_CLINICAL

"Joint hypermobility syndrome was found in 67.7% of patients with anxiety disorder but in only 10.1% of psychiatric and 12.5% of medical control subjects."

Direct case-control prevalence comparison; the paper's own "anxiety disorder" group here is entirely composed of the panic disorder/agoraphobia patients recruited for the study, per its method section.

PMID:9812121 (SUPPORT, direct)

Source: HUMAN_CLINICAL

"On the basis of statistical analysis, patients with anxiety disorder were over 16 times more likely than control subjects to have joint laxity."

The paper's own direct characterization of effect size; no single precise odds ratio value is given in the abstract, so this is recorded as supporting context rather than a numeric metric.

Signal 3

Population:Case-control study, 55 untreated panic-disorder patients versus matched psychiatric, fibromyalgia, and healthy control groups (Spain).

Signal IDs: MONDO:0007523 dismech -> MONDO:0005383 dismech

Mapping notes:The abstract reports only a qualitative ranking and a within-group severity correlation, with no extractable prevalence, odds ratio, or confidence interval; recorded as a corroborating case-control replication rather than a quantitative metric.

Temporal: A before B: , B before A: , Same time:

OTHER:

CI: -

FDR:

No single quantitative metric extractable from the abstract: joint hypermobility syndrome was reported as more frequent in the panic-disorder group than in each of the three control groups, with a significant within-group correlation between hypermobility severity and anxiety severity.

PMID:20118441 (SUPPORT)

Source: HUMAN_CLINICAL

"JHS was more frequent among panic-disorder than among psychiatric patients, the healthy group, or the fibromyalgia group. In the panic-disorder group, there was a significant correlation between severity of JHS and anxiety."

A third, independent case-control replication against three different control populations, plus a severity-severity correlation within the panic-disorder group.

Signal 4

Population:Prospective cohort study, 158 subjects aged 16-20 years recruited from the general population of a Spanish rural town, followed for 15 years; subjects with anxiety disorders at baseline excluded from follow-up analysis.

Signal IDs: MONDO:0007523 dismech -> MONDO:0005383 dismech

Mapping notes:This is the strongest available signal for this pair: a prospective cohort with joint hypermobility syndrome assessed at baseline, before any panic/agoraphobia diagnosis, and incident diagnosis assessed 15 years later. This is what justifies recording directionality as A_BEFORE_B at the entry level rather than UNKNOWN, unlike most cross-sectional case-control signals for this and other hEDS comorbidity pairs.

Temporal: A before B: , B before A: , Same time:

RR: 22.3

CI: 4.6 - 108.7

FDR:

Relative risk of incident panic/agoraphobia disorder (as main diagnosis) at 15-year follow-up, joint hypermobility syndrome group versus non-JHS group. Reported by the source as P<.0001, an upper bound not recorded as a point-value p_value here.

OTHER: 41.4

CI: -

FDR:

Cumulative incidence (not point prevalence) of panic/agoraphobia at 15-year follow-up in the JHS-at-baseline group.

OTHER: 1.9

CI: -

FDR:

Cumulative incidence (not point prevalence) of panic/agoraphobia at 15-year follow-up in the non-JHS control group.

PMID:21762833 (SUPPORT)

Source: HUMAN_CLINICAL

"Cumulative incidence of panic/agoraphobia disorder at follow-up, as main diagnosis, was significantly higher for the JHS group (41.4%) than for the control group (1.9%), with a relative risk of 22.3 [95% confidence interval (CI) 4.6-108.7, P<.0001] (Number Needed to Treat [NNT] 3, 95% CI 2.9-2.3)."

The prospective, baseline-to-follow-up quantification of risk, establishing temporal precedence of joint hypermobility syndrome over incident panic/agoraphobia.

Signal 5

Population:Systematic review of MEDLINE, PsycINFO, LILACS, and SciELO through December 2011; 17 studies included.

Signal IDs: MONDO:0007523 dismech -> MONDO:0005383 dismech

Temporal: A before B: , B before A: , Same time:

OTHER:

CI: -

FDR:

Narrative synthesis across 17 heterogeneous studies; no pooled quantitative effect size reported in the abstract.

PMID:22729449 (SUPPORT)

Source: HUMAN_CLINICAL

"Panic disorder/agoraphobia was the anxiety disorder associated with JH in several studies."

The systematic review's own synthesis across the case-control and cohort literature above, naming panic disorder/agoraphobia specifically rather than anxiety disorders in general.

Signal 6

Population:ICEES KG snapshot 8-20-2024 (RENCI/UNC).

Signal IDs: MONDO:0007523 dismech -> MONDO:0005383 dismech

Mapping notes:Searched: the local ICEES KG snapshot (rebuilt with `just icees-refresh`) contains only 226 nodes total, a small set of UNC-Health cohort-specific concepts. hEDS (MONDO:0007523) does not appear among them -- confirmed by grepping the decompressed node list directly (same check performed for the hEDS-POTS comorbidity entry). No ICEES signal exists for this pair in the current snapshot; recorded here rather than silently omitted.

Temporal: A before B: , B before A: , Same time:

Hypotheses

Hypothesis (the "neurovisceral phenotype" model, developed substantially around this specific pairing): connective-tissue laxity in hEDS is accompanied by altered autonomic/interoceptive signaling and heightened amygdala and insular cortex reactivity to threat-related stimuli. Because panic disorder is itself centrally defined by recurrent, acute misinterpretation of interoceptive (bodily) signals as threatening, this constitutional interoceptive/autonomic difference is proposed to lower the threshold for panic attacks specifically, more than for anxiety disorders without a prominent interoceptive-misappraisal component. The precise causal chain from connective-tissue collagen abnormality to altered central threat processing is not established.

PMID:20963520 (SUPPORT, review synthesis)

Source: HUMAN_CLINICAL

"the most significant and important association between joint hypermobility syndrome (JHS) and any other disorder from a clinical point of view is with panic disorder"

A dedicated review of the joint-hypermobility/anxiety literature singles out panic disorder as the specific, clinically significant association, distinguishing it from anxiety disorders in general.

PMID:25713509 (SUPPORT, indirect, review synthesis)

Source: HUMAN_CLINICAL

"In a recent functional neuroimaging study of healthy volunteers, hypermobile, compared to non-hypermobile, participants displayed heightened neural reactivity to sad and angry scenes within brain regions implicated in anxious feeling states, notably insular cortex (Mallorqui-Bague et al., 2014)."

The structural/functional neuroimaging correlate proposed to underlie the hypermobility-anxiety association generally, and cited here as the basis for the panic-specific interoceptive-threshold hypothesis.

PMID:8464956 (SUPPORT, indirect, primary result)

Source: HUMAN_CLINICAL

The founding case-control study establishes that the association is specific to panic-spectrum and phobic disorders and explicitly does not extend to generalized anxiety disorder or depression, supporting a mechanism tied to acute/interoceptive threat response rather than anxiety or mood disturbance in general.

Pathophysiology:

Heightened Amygdala and Insular Threat Reactivity: Functional neuroimaging in hypermobile individuals shows heightened amygdala and insular cortex reactivity to threat-related emotional stimuli, proposed as the neural substrate underlying the association between joint hypermobility and anxiety/panic. A separate, more speculative pathway proposed in the same source involves a perturbation of autonomic afferent feedback, distinct from amygdala/insular reactivity itself and not independently evidenced here.

PMID:25713509 (SUPPORT, direct, review synthesis)

Source: HUMAN_CLINICAL

"These neuroimaging data implicate the amygdala and insular cortices as the most likely neural substrate underlying the association between of hypermobility, clinical anxiety and psychosomatic disorders."

The review's own synthesis naming the amygdala and insula as the proposed neural substrate for the hypermobility-anxiety association.

PMID:25713509 (SUPPORT, indirect, review synthesis)

Source: HUMAN_CLINICAL

"Speculatively, potential mechanisms that may further account for the mediating role of amygdala between anxiety and hypermobility include heightened susceptibility to the threat of pain and a perturbation of autonomic afferent feedback"

The review's own explicitly speculative extension beyond the amygdala/insular neuroimaging finding, naming autonomic afferent feedback as a separate proposed mechanism.

Lowered Panic-Attack Threshold via Interoceptive Misappraisal: Proposed downstream consequence, not directly demonstrated for joint-hypermobility carriers specifically: heightened threat reactivity in amygdala/insular circuitry is proposed to increase the propensity for panic attacks, which are centrally defined by the acute misinterpretation of interoceptive (bodily) signals as dangerous.

Biological processes:

PMID:20963520 (SUPPORT, indirect, review synthesis)

Source: HUMAN_CLINICAL

"the most significant and important association between joint hypermobility syndrome (JHS) and any other disorder from a clinical point of view is with panic disorder"

Supports panic disorder specifically, rather than anxiety in general, as the clinical endpoint of this node; does not itself establish the amygdala/insula-to-panic-threshold mechanistic step.

Raw YAML

Show YAML

name: com_Hypermobile_Ehlers-Danlos_Syndrome__Panic_Disorder
creation_date: '2026-09-24T00:00:00Z'
curation_status: CANDIDATE
notes: >-
  Panic disorder/agoraphobia is the single anxiety disorder most consistently
  and specifically associated with joint hypermobility across a body of
  case-control and cohort literature spanning three decades, largely from one
  research group (Bulbena, Martín-Santos and colleagues, Barcelona). A 1993
  case-control study found panic disorder, agoraphobia, and simple phobia --
  but not generalized anxiety disorder, dysthymic disorder, or major
  depression -- were specifically elevated in joint hypermobility syndrome
  (age- and sex-adjusted OR 10.7). A 1998 case-control study replicated this
  in patients newly diagnosed with panic disorder/agoraphobia (67.7% had
  joint hypermobility syndrome versus 10.1%-12.5% of controls). A 2010
  case-control study replicated the association against three separate
  control groups (psychiatric, fibromyalgia, and healthy). A 2011 prospective
  15-year cohort study established temporal precedence: joint hypermobility
  syndrome assessed at baseline (ages 16-20) predicted a markedly higher
  cumulative incidence of panic/agoraphobia at follow-up (relative risk
  22.3). A 2012 systematic review of 17 studies concluded panic
  disorder/agoraphobia was the anxiety disorder most consistently linked to
  joint hypermobility across the literature. These studies predate the 2017
  hEDS diagnostic criteria and use Beighton-criteria "joint hypermobility
  syndrome" (JHS), the diagnostic predecessor that was folded into the
  hypermobility spectrum disorder/hEDS nosology; they are treated here as the
  closest available literature for the current hEDS diagnosis. Directionality
  is recorded as A_BEFORE_B on the strength of the 2011 prospective cohort,
  in contrast to most other hEDS comorbidity entries in this KB where only
  cross-sectional evidence exists. No ICEES KG signal exists for this pair:
  hEDS (MONDO:0007523) is not a node in the ICEES KG snapshot at all
  (confirmed while curating the hEDS-POTS comorbidity entry).

disease_a:
  slug: Hypermobile_Ehlers-Danlos_Syndrome
  preferred_term: Ehlers-Danlos syndrome, hypermobility type
  term:
    id: MONDO:0007523
    label: Ehlers-Danlos syndrome, hypermobility type

disease_b:
  slug: Panic_Disorder
  preferred_term: panic disorder
  term:
    id: MONDO:0005383
    label: panic disorder

directionality: A_BEFORE_B
effect_direction: RISK

hypotheses:
- description: >-
    Hypothesis (the "neurovisceral phenotype" model, developed substantially
    around this specific pairing): connective-tissue laxity in hEDS is
    accompanied by altered autonomic/interoceptive signaling and heightened
    amygdala and insular cortex reactivity to threat-related stimuli. Because
    panic disorder is itself centrally defined by recurrent, acute
    misinterpretation of interoceptive (bodily) signals as threatening, this
    constitutional interoceptive/autonomic difference is proposed to lower
    the threshold for panic attacks specifically, more than for anxiety
    disorders without a prominent interoceptive-misappraisal component. The
    precise causal chain from connective-tissue collagen abnormality to
    altered central threat processing is not established.
  evidence:
  - reference: PMID:20963520
    reference_title: "Joint hypermobility and anxiety: the state of the art."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "the most significant and important association between joint hypermobility syndrome (JHS) and any other disorder from a clinical point of view is with panic disorder"
    explanation: >-
      A dedicated review of the joint-hypermobility/anxiety literature
      singles out panic disorder as the specific, clinically significant
      association, distinguishing it from anxiety disorders in general.
  - reference: PMID:25713509
    reference_title: "Neurovisceral phenotypes in the expression of psychiatric symptoms."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "In a recent functional neuroimaging study of healthy volunteers, hypermobile, compared to non-hypermobile, participants displayed heightened neural reactivity to sad and angry scenes within brain regions implicated in anxious feeling states, notably insular cortex (Mallorqui-Bague et al., 2014)."
    explanation: >-
      The structural/functional neuroimaging correlate proposed to underlie
      the hypermobility-anxiety association generally, and cited here as the
      basis for the panic-specific interoceptive-threshold hypothesis.
    directness: INDIRECT
  - reference: PMID:8464956
    reference_title: "Anxiety disorders in the joint hypermobility syndrome."
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "DSM-III-R diagnoses of panic disorder, agoraphobia, and simple phobia, but not generalized anxiety disorder, dysthymic disorder, or major depression were found to be highly associated with JHS (age- and sex-adjusted odds ratio = 10.7)."
    explanation: >-
      The founding case-control study establishes that the association is
      specific to panic-spectrum and phobic disorders and explicitly does
      not extend to generalized anxiety disorder or depression, supporting a
      mechanism tied to acute/interoceptive threat response rather than
      anxiety or mood disturbance in general.
    directness: INDIRECT
  pathophysiology:
  - name: Heightened Amygdala and Insular Threat Reactivity
    description: >-
      Functional neuroimaging in hypermobile individuals shows heightened
      amygdala and insular cortex reactivity to threat-related emotional
      stimuli, proposed as the neural substrate underlying the association
      between joint hypermobility and anxiety/panic. A separate, more
      speculative pathway proposed in the same source involves a
      perturbation of autonomic afferent feedback, distinct from
      amygdala/insular reactivity itself and not independently evidenced
      here.
    biological_scale: TISSUE
    locations:
    - preferred_term: amygdala
      term:
        id: UBERON:0001876
        label: amygdala
    - preferred_term: insula
      term:
        id: UBERON:0002022
        label: insula
    downstream:
    - target: Lowered Panic-Attack Threshold via Interoceptive Misappraisal
      causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      description: >-
        Proposed but not mechanistically demonstrated: heightened
        amygdala/insular threat reactivity is proposed to translate into a
        lowered threshold for the acute interoceptive misappraisal that
        defines a panic attack.
    evidence:
    - reference: PMID:25713509
      reference_title: "Neurovisceral phenotypes in the expression of psychiatric symptoms."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "These neuroimaging data implicate the amygdala and insular cortices as the most likely neural substrate underlying the association between of hypermobility, clinical anxiety and psychosomatic disorders."
      explanation: >-
        The review's own synthesis naming the amygdala and insula as the
        proposed neural substrate for the hypermobility-anxiety
        association.
      directness: DIRECT
    - reference: PMID:25713509
      reference_title: "Neurovisceral phenotypes in the expression of psychiatric symptoms."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "Speculatively, potential mechanisms that may further account for the mediating role of amygdala between anxiety and hypermobility include heightened susceptibility to the threat of pain and a perturbation of autonomic afferent feedback"
      explanation: >-
        The review's own explicitly speculative extension beyond the
        amygdala/insular neuroimaging finding, naming autonomic afferent
        feedback as a separate proposed mechanism.
      directness: INDIRECT
  - name: Lowered Panic-Attack Threshold via Interoceptive Misappraisal
    description: >-
      Proposed downstream consequence, not directly demonstrated for
      joint-hypermobility carriers specifically: heightened threat
      reactivity in amygdala/insular circuitry is proposed to increase the
      propensity for panic attacks, which are centrally defined by the
      acute misinterpretation of interoceptive (bodily) signals as
      dangerous.
    biological_scale: ORGANISM
    biological_processes:
    - preferred_term: heightened fear response to bodily/interoceptive signals
      term:
        id: GO:0042596
        label: fear response
      modifier: INCREASED
    evidence:
    - reference: PMID:20963520
      reference_title: "Joint hypermobility and anxiety: the state of the art."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "the most significant and important association between joint hypermobility syndrome (JHS) and any other disorder from a clinical point of view is with panic disorder"
      explanation: >-
        Supports panic disorder specifically, rather than anxiety in
        general, as the clinical endpoint of this node; does not itself
        establish the amygdala/insula-to-panic-threshold mechanistic step.
      directness: INDIRECT

association_signals:
- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005383
  population: >-
    Case-control study, 114 cases of joint hypermobility syndrome diagnosed
    at a rheumatology outpatient clinic (Hospital del Mar, Barcelona) versus
    59 controls from the same clinic.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: AOR
      metric_value: 10.7
      notes: >-
        Age- and sex-adjusted odds ratio for panic disorder, agoraphobia, and
        simple phobia in JHS versus controls, as reported by the source.
        Generalized anxiety disorder, dysthymic disorder, and major
        depression were explicitly not associated.
    evidence:
    - reference: PMID:8464956
      reference_title: "Anxiety disorders in the joint hypermobility syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "DSM-III-R diagnoses of panic disorder, agoraphobia, and simple phobia, but not generalized anxiety disorder, dysthymic disorder, or major depression were found to be highly associated with JHS (age- and sex-adjusted odds ratio = 10.7)."
      explanation: >-
        Directly quantifies the panic/phobic-specific association and its
        adjusted odds ratio.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005383
  population: >-
    Case-control study, 99 newly diagnosed, untreated patients with panic
    disorder, agoraphobia, or both versus 99 psychiatric controls and 64
    medical controls (Spain).
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: PREVALENCE
      metric_value: 67.7
      notes: Prevalence of joint hypermobility syndrome in the panic disorder/agoraphobia group.
    - metric_type: PREVALENCE
      metric_value: 10.1
      notes: Prevalence of joint hypermobility syndrome in the psychiatric control group.
    - metric_type: PREVALENCE
      metric_value: 12.5
      notes: Prevalence of joint hypermobility syndrome in the medical control group.
    evidence:
    - reference: PMID:9812121
      reference_title: "Association between joint hypermobility syndrome and panic disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Joint hypermobility syndrome was found in 67.7% of patients with anxiety disorder but in only 10.1% of psychiatric and 12.5% of medical control subjects."
      explanation: >-
        Direct case-control prevalence comparison; the paper's own "anxiety
        disorder" group here is entirely composed of the panic
        disorder/agoraphobia patients recruited for the study, per its
        method section.
    - reference: PMID:9812121
      reference_title: "Association between joint hypermobility syndrome and panic disorder."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "On the basis of statistical analysis, patients with anxiety disorder were over 16 times more likely than control subjects to have joint laxity."
      explanation: >-
        The paper's own direct characterization of effect size; no single
        precise odds ratio value is given in the abstract, so this is
        recorded as supporting context rather than a numeric metric.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005383
  population: >-
    Case-control study, 55 untreated panic-disorder patients versus matched
    psychiatric, fibromyalgia, and healthy control groups (Spain).
  mapping_notes: >-
    The abstract reports only a qualitative ranking and a within-group
    severity correlation, with no extractable prevalence, odds ratio, or
    confidence interval; recorded as a corroborating case-control replication
    rather than a quantitative metric.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: OTHER
      notes: >-
        No single quantitative metric extractable from the abstract: joint
        hypermobility syndrome was reported as more frequent in the
        panic-disorder group than in each of the three control groups, with
        a significant within-group correlation between hypermobility
        severity and anxiety severity.
    evidence:
    - reference: PMID:20118441
      reference_title: "Association between joint hypermobility syndrome and panic disorder: a case-control study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "JHS was more frequent among panic-disorder than among psychiatric patients, the healthy group, or the fibromyalgia group. In the panic-disorder group, there was a significant correlation between severity of JHS and anxiety."
      explanation: >-
        A third, independent case-control replication against three
        different control populations, plus a severity-severity correlation
        within the panic-disorder group.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005383
  population: >-
    Prospective cohort study, 158 subjects aged 16-20 years recruited from
    the general population of a Spanish rural town, followed for 15 years;
    subjects with anxiety disorders at baseline excluded from follow-up
    analysis.
  mapping_notes: >-
    This is the strongest available signal for this pair: a prospective
    cohort with joint hypermobility syndrome assessed at baseline, before any
    panic/agoraphobia diagnosis, and incident diagnosis assessed 15 years
    later. This is what justifies recording directionality as A_BEFORE_B at
    the entry level rather than UNKNOWN, unlike most cross-sectional
    case-control signals for this and other hEDS comorbidity pairs.
  directionality: A_BEFORE_B
  statistics:
    metrics:
    - metric_type: RR
      metric_value: 22.3
      metric_ci_lower: 4.6
      metric_ci_upper: 108.7
      notes: >-
        Relative risk of incident panic/agoraphobia disorder (as main
        diagnosis) at 15-year follow-up, joint hypermobility syndrome group
        versus non-JHS group. Reported by the source as P<.0001, an upper
        bound not recorded as a point-value p_value here.
    - metric_type: OTHER
      metric_value: 41.4
      notes: Cumulative incidence (not point prevalence) of panic/agoraphobia at 15-year follow-up in the JHS-at-baseline group.
    - metric_type: OTHER
      metric_value: 1.9
      notes: Cumulative incidence (not point prevalence) of panic/agoraphobia at 15-year follow-up in the non-JHS control group.
    evidence:
    - reference: PMID:21762833
      reference_title: "Joint hypermobility syndrome is a risk factor trait for anxiety disorders: a 15-year follow-up cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cumulative incidence of panic/agoraphobia disorder at follow-up, as main diagnosis, was significantly higher for the JHS group (41.4%) than for the control group (1.9%), with a relative risk of 22.3 [95% confidence interval (CI) 4.6-108.7, P<.0001] (Number Needed to Treat [NNT] 3, 95% CI 2.9-2.3)."
      explanation: >-
        The prospective, baseline-to-follow-up quantification of risk,
        establishing temporal precedence of joint hypermobility syndrome
        over incident panic/agoraphobia.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005383
  population: >-
    Systematic review of MEDLINE, PsycINFO, LILACS, and SciELO through
    December 2011; 17 studies included.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: OTHER
      notes: >-
        Narrative synthesis across 17 heterogeneous studies; no pooled
        quantitative effect size reported in the abstract.
    evidence:
    - reference: PMID:22729449
      reference_title: "Anxiety and joint hypermobility association: a systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Panic disorder/agoraphobia was the anxiety disorder associated with JH in several studies."
      explanation: >-
        The systematic review's own synthesis across the case-control and
        cohort literature above, naming panic disorder/agoraphobia
        specifically rather than anxiety disorders in general.

- source: ICEES
  method: EHR_COHORT_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005383
  population: ICEES KG snapshot 8-20-2024 (RENCI/UNC).
  mapping_notes: >-
    Searched: the local ICEES KG snapshot (rebuilt with `just icees-refresh`)
    contains only 226 nodes total, a small set of UNC-Health cohort-specific
    concepts. hEDS (MONDO:0007523) does not appear among them -- confirmed
    by grepping the decompressed node list directly (same check performed
    for the hEDS-POTS comorbidity entry). No ICEES signal exists for this
    pair in the current snapshot; recorded here rather than silently
    omitted.
  directionality: UNKNOWN

Source:GitHub