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

Abstract

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 shorted Spielberger Trait Anxiety measure, we analyzed: (1) a total trait anxiety score based on summing responses to all ten items; and (2) a GAD symptoms score restricted to the three items tapping diagnostic features of GAD as defined by DSM-V. We first calculated the heritability due to common variants (h2SNP) 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=4.18×10−8) 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 GWAS revealed 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.

A Major Role for Common Genetic Variation in Anxiety Disorders

“…Our results suggest that a large proportion of heritable variance in anxiety is attributable to common genetic variants, with the effects spread over many hundreds or thousands of loci 53 . Our h 2 SNP estimates are also much higher than those derived from previous studies of anxiety 11,22 , which may reflect the homogeneity of the UK Biobank sample in terms of assessment, sampling, and genotyping.…”

“…Finally, a SNP within RBFOX1 was found to be significantly associated with anxiety sensitivity in a small cohort of twins 21 . The proportion of variation in generalised anxiety disorder symptoms explained by individual genetic variation (SNP heritability; h 2 SNP) was estimated at 7.2% in a modest sample (n=12 282) of Hispanic/Latino adults 22 , and 14% in the meta-analysis described above, which consisted largely of individuals with European ancestry 11 .…”

Anxiety genetics: Dispatches from the frontier

“…Dunn et al [2016] report the largest single GWAS focused on generalized anxiety. Their report is also notable for addressing another gap in psychiatric genomic research: the vast majority of GWAS have been restricted to samples of European ancestry.…”

“…Their report is also notable for addressing another gap in psychiatric genomic research: the vast majority of GWAS have been restricted to samples of European ancestry. Dunn et al [2016] examined a unique, population-based sample of nearly 13,000 adults in the Hispanic Community Health Study/Study of Latinos (HCHS/ SOL). They derived a quantitative measure of generalized anxiety from GAD symptoms captured by a self-report measure of trait anxiety.…”

Genetic Polymorphisms and Generalized Anxiety Disorder: a systematic review

“…A significant number of genomic loci associated with symptoms of this disorder have been reported. 13 Association studies correlate allelic and genotypic frequencies between mentally affected individuals bearing no familial relations vs. mentally healthy controls. Such association studies aim to identify susceptibility loci.…”