Meta-analysis of genome-wide association studies of anxiety disorders

Abstract

Anxiety disorders, namely generalized anxiety disorder, panic disorder, and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based upon clinical presentation, anxiety disorders likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based anxiety disorders, we applied two phenotypic approaches: (1) comparisons between categorical anxiety disorder cases and super-normal controls, and (2) quantitative phenotypic factor scores derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65×10−8); for factor scores, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86×10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of anxiety disorders.

Genetic risk variants for social anxiety

“…We used LD score regression (LDSC) ] to test the genetic correlation between social anxiety and other traits in European samples using recently published meta-analytic GWAS for anxiety disorders [Otowa et al 2016], neuroticism [Genetics of Personality et al 2015], and extraversion [van den Berg et al 2016], respectively. As a negative control, we also tested the genetic correlation between social anxiety and Alzheimer's disease [Lambert et al 2013].…”

“…Berg et al 2016] (r g = -0.52, se = 0.22, p = 0.02) in European samples. Genetic correlations with neuroticism [Genetics of Personality et al 2015] and with an anxiety disorders quantitative factor score (derived from a multivariate analysis combining information across various anxiety disorder clinical phenotypes) [Otowa et al 2016] were of smaller magnitude (r g = 0.05 to 0.22) and not statistically significant (Table 4). Genetic correlation with Alzheimer's disease [Lambert et al 2013], intended as a "negative control", was, as anticipated, small and not statistically significant (r g = 0.06, se = 0.23, p = 0.79).…”

“…We also explored the genetic relationship of social anxiety to an anxiety disorder factor score derived in a large anxiety disorder GWAS meta-analysis [Otowa et al 2016]. As a "negative control" we also determined the genetic relationship of social anxiety with Alzheimer's disease [Lambert et al 2013].…”

Separate and combined effects of genetic variants and pre-treatment whole blood gene expression on response to exposure-based cognitive behavioural therapy for anxiety disorders

“…Studying anxiety disorders as a heterogeneous group has been effective in genomics (Otowa et al 2016). However, combining groups increases heterogeneity, partially negating the increased power from the enlarged sample size.…”

Anxiety genetics: Dispatches from the frontier

“…Sadly, the anxiety disorders have remained largely neglected in terms of genomic research. We are only beginning to see the appearance of large-scale genomewide association analyses identifying significant common variant associations [Otowa et al, 2016]. We have just begun to clear the brush from the wilderness of anxiety disorder genetics.…”