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 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. © 2016 Wiley Periodicals, Inc.

Keywords: Hispanics/Latinos; anxiety; genetic association study.

Figure 1

Quantile-quantile (QQ) plots and Manhattan plots for GAD symptoms score from the Hispanic Community Health Study/Study of Latinos The quantile–quantile plots (“QQ-plots”), which present the observed by expected P-values on the -log10 scale, indicate conformity of the observed results to what would be expected under the null. In the Manhattan plots, the x-axis is the chromosomal position and the y-axis is the -log10 p-value for the association between each SNP and core anxiety symptoms derived from the linear regression model. The dotted line shows the genome-wide significance level (5×10⁻⁸). The displayed p-value corresponds to SNPs with effective N > 30.

Figure 2

Regional association plot for the top SNP (rs78602344) identified in the analysis excluding medication users The regional association plot was generated using LocusZoom (http://csg.sph.umich.edu/locuszoom/) The left-side y-axis refers to the -log of the p-value corresponding to the test of association between each SNP (denoted as a colored dot, if genotyped, or X, if imputed) and GAD symptoms. SNPs are colored based on the level of linkage disequilibrium (LD) between each SNP and the index, genotyped, SNP (purple diamond). r² values are determined based on the HCHS/SOL data.