Genetic Epidemiology of Anxiety Disorders

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Clinical Question: What are the roles of genetic and environmental factors in the etiology of anxiety disorders?

Reference: Hettema J, Neale M, and Kendler K. 2001. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 158:1568-78

Background: Anxiety disorders are very common, with a lifetime prevalence of up to 25%.

Objective: To assess the evidence for heritability of anxiety disorders: 1) What is the magnitude of familial aggregation in anxiety disorders? 2) What are the relative contributions of genetic and environmental factors in the etiology of anxiety disorders?

Methods:

Study sources: MEDLINE, references from manuscripts identified in the MEDLINE search

Types of studies included: epidemiologic studies; twin and family studies (case-control)

Inclusion criteria: published family and twin studies with standardized diagnostic criteria, systematic study of probands and their relatives, direct interviews with most subjects, investigators performing interviews blinded to proband status, and inclusion of a control group in family studies.

Studies screened vs. accepted: 10 panic disorder, 5 GAD, 8 phobia, 5 OCD studies included. Number of studies screened and not included was not discussed.

Patient population: family studies were clinic-based study groups, twin studies community-based.

Data collection: Studies were excluded if they failed to meet above inclusion criteria.

Data analysis: Family and twin data combined into aggregate family and twin groups for each disorder. For family studies, odds ratios were calculated using the Mantel-Haenszel method on the SAS routine proc freq. For twin studies structural equation modeling performed. This provides estimates of variance in liability to a disorder attributable to additive genetic (a2), common familial environmental (c2), and individual-specific environmental factors (e2)

Validity:

Focused clinical question? No, this study was ambitious in attempting to characterize both the magnitude of familial aggregation of anxiety disorders and relative contribution of genetic and environmental factors in the etiology of anxiety disorders.

Inclusion criteria appropriate? Yes, however some inclusion criteria were then relaxed to include more studies. Relevant studies omitted? Possibly, although relaxation of inclusion criteria allowed more studies to be included.

Studies appraised for validity? No

Assessments of studies reproducible? No, as the authors made assumptions regarding environmental factors being similar within families, and that clinical and community based study groups could be aggregated. Some but not all assumptions were tested for validity.

Results:

• Panic disorder:
  • 5 family studies support familial aggregation (p<0.0001), OR 5 (95% CI 3-8.2)
  • 3 twin studies most consistent with additive genetic and individual-specific environmental factor models (not common familial environment)
• GAD
  • 1 blinded family study, 1 unblinded, both support familial aggregation (p<0.0001), OR 6.1 (95% CI 2.5-14.9)
  • 2 twin studies attribute additive genetics and individual-specific environment in both genders, small role for common familial environment in women only
• Phobias
  • 4 family studies support familial aggregation (p<0.0001), OR 4.1 (95% CI 2.7-6.1)
  • 1 twin study suggests additive genetic model for social phobia, agoraphobia, and animal phobias.
  • Inconsistent results across different phobias.
• OCD
  • 4 family studies support familial aggregation (p<0.0001), OR 4 (95% CI 2.2-7.1)
  • No twin studies met inclusion criteria.

Strengths – Interesting, though broad clinical questions regarding extremely common disorders.

Weaknesses – Small number of studies available for meta-analysis. Limited information provided regarding patient populations studied or about studies that were excluded. Assumptions made regarding environmental similarities in family and twin studies that could not be tested for validity.

CLINICAL BOTTOM LINE:

Anxiety disorders do aggregate in families. The predominant source of familial risk does appear to be genetic; however data are limited that would discern genetic vs. common familial environmental sources (ie adoption studies). Estimated heritabilities across disorders are in 30-40% range, which is lower than schizophrenia and bipolar disorder.

Critically Appraised Topic -- Kristen Shirey –6/26/06