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Neuropeptide Y (NPY) has been found to be anxiolytic in animals and humans. A recent study found NPY expression to be inversely correlated with trait anxiety. We examined whether rs16147, a functional single nucleotide polymorphism in the promoter region of NPY, moderated the relationship between hurricane exposure and risk for generalized anxiety disorder (GAD) in an epidemiologic sample of adults living in areas affected by the 2004 Florida Hurricanes.Data from this study comes from 616 adults from the 2004 Florida Hurricanes study who returned buccal DNA samples via mail. Selection of participants occurred via random digit-dial procedures. Participants were interviewed via telephone about hurricane exposure and posthurricane GAD symptoms. The outcome measure was DSM-IV GAD diagnosis, assessed via structured interview.Rs16147 in NPY was associated with increased risk of GAD diagnosis under conditions of high hurricane exposure (P<.01). This gene by environment interaction remained significant after adjustment for sex, ancestry (as determined by Bayesian clustering of genotypes), and age.NPY rs16147 modifies risk of postdisaster GAD under conditions of high stressor (hurricane) exposure. This is the first demonstration of gene–environment interaction for this locus.