Unravelling Sex Differences in the Genetic Architecture of Anxiety: A Genome-Wide Association Study in the UK Biobank
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Background
Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced.
Methods
This study investigated the genetic basis of these differences using sex-specific genome-wide association studies (GWAS). GWAS were conducted separately in females (47,054 cases, 57,027 controls) and males (23,819 cases, 55,030 controls) within the UK Biobank. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications.
Results
In females, 10 lead SNPs were significantly associated with anxiety, compared to four in males. Among these, three lead SNPs in females and two in males demonstrated significantly different effect sizes across sexes. In addition, SNP-based heritability estimates were significantly different and gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. However, whole-genome analyses, including genetic correlations across sexes and PGS predictions, revealed no significant genetic differences between the sexes. Sex combined GWAS of several traits showed a trend toward sex differences with anxiety in genetic correlation analysis. Sex-specific GWAS on waist-to-hip ratio (WHR) adjusted for BMI enabled separate genetic correlation analyses with anxiety, revealing significant sex differences that were not observed in the combined GWAS.
Conclusions
This study is the first sex-specific GWAS of anxiety. While the overall genetic architecture of anxiety is largely shared between sexes, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analysing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.
