Brain transcriptome-wide association studies in diverse ancestral populations reveal genes implicated in an anxiety-related phenotype.

Anxiety is the most prevalent form of mental illness in the United States. We aimed to identify genetic variation underlying anxiety in diverse ancestral populations through integrating genomic and brain transcriptomic data. We analyzed genome-wide association study (GWAS) summary statistics, using the "Worrier/Anxious Feelings" phenotype from Pan-UK Biobank. We identified 67 independent significant loci in the combined meta-analysis of six ancestral populations (META-GWAS) and 1 locus in the African (AFR) GWAS (P < 5.0 × 10-8). We performed transcriptome-wide association studies (TWAS) and identified 683 significantly associated genes in the META-TWAS, and 1 gene in the AFR-TWAS (P < 3.85 × 10-6). Namely, we identified CADM2 in the META-TWAS and its predicted paralog SMAGP in the AFR-TWAS. The genes identified in TWAS were enriched for variants associated with autism, neuroticism, and schizophrenia, highlighting shared genetic architecture among neuropsychiatric traits. In this study, we present these loci and genes as potential targets for future research on anxiety-related phenotypes.