Genome-wide association study of generalized anxiety symptoms in the Hispanic Community Health Study/Study of Latinos

Although generalized anxiety disorder (GAD) is heritable and aggregates in families, no genomic loci associated with GAD have been reported. We aimed to discover potential loci by conducting a genome-wide analysis of GAD symptoms in a large, population-based sample of Hispanic/Latino adults. Data came from 12,282 participants (aged 18–74) in the Hispanic Community Health Study/Study of Latinos. Using a shortened Spielberger Trait Anxiety measure, we analyzed the following: (i) a GAD symptoms score restricted to the three items tapping diagnostic features of GAD as defined by DSM-V; and (ii) a total trait anxiety score based on summing responses to all ten items. We first calculated the heritability due to common variants (h² _SNP) and then conducted a genome-wide association study (GWAS) of GAD symptoms. Replication was attempted in three independent Hispanic cohorts (Multi-Ethnic Study of Atherosclerosis, Women's Health Initiative, Army STARRS). The GAD symptoms score showed evidence of modest heritability (7.2%; P = 0.03), while the total trait anxiety score did not (4.97%; P = 0.20). One genotyped SNP (rs78602344) intronic to thrombospondin 2 (THBS2) was nominally associated (P = 5.28 × 10⁻⁸) in the primary analysis adjusting for psychiatric medication use and significantly associated with the GAD symptoms score in the analysis excluding medication users (P = 4.18 × 10⁻⁸). However, meta-analysis of the replication samples did not support this association. Although we identified a genome-wide significant locus in this sample, we were unable to replicate this finding. Evidence for heritability was also only detected for GAD symptoms, and not the trait anxiety measure, suggesting differential genetic influences within the domain of trait anxiety.