CONNECTING GENETIC RISK AND BRAIN STRUCTURE IN ANXIETY DISORDERS

Anxiety disorders have been associated with structural differences in various brain regions, including alterations in cortical and subcortical morphology and white matter integrity. Despite growing evidence from neuroimaging studies, the degree to which these neural features are genetically linked to anxiety remains insufficiently understood. Elucidating the shared genetic architecture between anxiety and brain morphology is critical for uncovering the biological mechanisms that contribute to individual differences in vulnerability and expression of these conditions.

In this study, we investigated the shared genetic architecture between anxiety and brain structure by integrating genome-wide association data from PGC-Anxiety (N = 122,341) and imaging-genetic data from the UK Biobank. The neuroimaging data included 196 global and regional brain phenotypes derived from structural MRI and diffusion tensor imaging, covering cortical thickness, surface area, subcortical volumes, and measures of white matter microstructure such as fractional anisotropy and mean diffusivity.

To quantify the extent of shared genetic influences, we employed several complementary statistical approaches. Linkage disequilibrium score regression (LDSC) was used to estimate genome-wide genetic correlations between anxiety and brain morphology. MiXeR was applied to characterize the polygenic overlap, estimating the number of shared and trait-specific variants. Additionally, conditional false discovery rate (condFDR) analysis was conducted to identify genomic loci jointly associated with anxiety and brain phenotypes, increasing statistical power by leveraging pleiotropy and utilising mixed effect directions. All analyses were performed at both global and regional levels to identify brain structures most strongly implicated in the shared genetic architecture.

Our findings highlight significant genetic correlations and overlapping loci between anxiety and multiple brain phenotypes, providing novel insights into the biological pathways that underpin anxiety risk. These results suggest that structural variation in specific brain regions may reflect underlying genetic vulnerability to anxiety and could represent intermediate phenotypes that bridge genetic risk and clinical presentation.