Abstract
ContextAnxiety disorders are common, with a lifetime prevalence of 20% in the U.S., and are responsible for substantial burdens of disability, missed work days and health care utilization. To date, no causal genetic variants have been identified for anxiety, anxiety disorders, or related traits.ObjectiveTo investigate whether a phobic anxiety symptom score was associated with 3 alternative polygenic risk scores, derived from external genome-wide association studies of anxiety, an internally estimated agnostic polygenic score, or previously identified candidate genes.DesignLongitudinal follow-up study. Using linear and logistic regression we investigated whether phobic anxiety was associated with polygenic risk scores derived from internal, leave-one out genome-wide association studies, from 31 candidate genes, and from out-of-sample genome-wide association weights previously shown to predict depression and anxiety in another cohort.Setting and ParticipantsStudy participants (n = 11,127) were individuals from the Nurses' Health Study and Health Professionals Follow-up Study.Main Outcome MeasureAnxiety symptoms were assessed via the 8-item phobic anxiety scale of the Crown Crisp Index at two time points, from which a continuous phenotype score was derived.ResultsWe found no genome-wide significant associations with phobic anxiety. Phobic anxiety was also not associated with a polygenic risk score derived from the genome-wide association study beta weights using liberal p-value thresholds; with a previously published genome-wide polygenic score; or with a candidate gene risk score based on 31 genes previously hypothesized to predict anxiety.ConclusionThere is a substantial gap between twin-study heritability estimates of anxiety disorders ranging between 20–40% and heritability explained by genome-wide association results. New approaches such as improved genome imputations, application of gene expression and biological pathways information, and incorporating social or environmental modifiers of genetic risks may be necessary to identify significant genetic predictors of anxiety.
Highlights
Anxiety disorders, the most commonly occurring psychiatric disorders in the United States, account for a substantial burden of disability, increased health care utilization, and high absenteeism from work [1,2]
Phobic anxiety was not associated with a polygenic risk score derived from the genome-wide association study beta weights using liberal p-value thresholds; with a previously published genome-wide polygenic score; or with a candidate gene risk score based on 31 genes previously hypothesized to predict anxiety
To test the hypothesis that heritability of phobic anxiety can be explained by common single nucleotide polymorphisms (SNPs), we considered the variation in phobic anxiety that can be explained using genome-wide association studies (GWAS)-derived polygenic risk scores in genotyped sub-samples of women from the Nurses’ Health Study (NHS) and men from the Health Professionals Follow-up Study (HPFS)
Summary
The most commonly occurring psychiatric disorders in the United States, account for a substantial burden of disability, increased health care utilization, and high absenteeism from work [1,2]. Twin studies typically suggest heritability of anxiety disorders between 20–40% [3,4], and up to 50–55% for traits proposed as endophenotypes (e.g., neuroticism, behavioral inhibition) [5]. These twin study heritability estimates do not reveal anything about the genetic architecture of anxiety. Several hypotheses for the absence of confirmed loci have been posited, including the possibility that the heritability of anxiety is attributable to a large number of alleles each with effect sizes too small to detect in GWAS [17]. Evidence supporting a polygenic basis of anxiety was reported in a recent paper by Demirkan et al, in which ,2% of anxiety was predicted in independent samples using genome-wide polygenic risk scores derived from a GWAS of depression [18]
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