Background: The single nucleotide polymorphism rs4680 of the catechol-O-methyltransferase (COMT) gene has been implicated to be involved in the etiopathogenesis of panic. However, it remains unresolved whether rs4680 modifies the risk-association between early life stress and subsequent development of panic pathology.

Methods: The genotype of rs4680 was determined for n = 2242 adults with European ancestry from the Study of Health in Pomerania (SHIP, a regional longitudinal cohort study from northeastern Germany). Lifetime fearful spells, panic attacks and panic disorder were assessed according to DSM-IV in 2007-2010 (when participants were aged 29-89) using the Munich Composite International Diagnostic Interview (DIA-X/M-CIDI). Childhood adversities were assessed with the Childhood Trauma Questionnaire (CTQ).

Results: Logistic regressions with interaction terms (adjusted for sex and age) revealed that rs4680 interacted with total childhood adversity, emotional abuse and physical abuse in predicting panic disorder: Respective childhood adversities predicted panic disorder in carriers of the Val/Met or Met/Met genotype, but not Val/Val genotype. Moreover, a 3-way interaction was found between rs4680, emotional abuse and sex in predicting panic attacks: Emotional abuse predicted panic attacks among male carriers of the Val/Val genotype and female carriers of the Val/Met or Met/Met genotype, but not among male carriers of the Val/Met or Met/Met genotype or female carriers of the Val/Val genotype.

Limitations: Genotype data were derived by imputation. Childhood adversities and panic were assessed retrospectively.

Conclusions: Especially (female) carriers of the Val/Met or Met/Met genotype of rs4680 might profit from targeted early interventions to prevent the onset of panic after childhood adversities.