Genome-wide meta-analysis, functional genomics and integrative analyses implicate new risk genes and therapeutic targets for anxiety disorders.

Anxiety disorders are the most prevalent mental disorders. However, the genetic etiology of anxiety disorders remains largely unknown. Here we conducted a genome-wide meta-analysis on anxiety disorders by including 74,973 (28,392 proxy) cases and 400,243 (146,771 proxy) controls. We identified 14 risk loci, including 10 new associations near CNTNAP5, MAP2, RAB9BP1, BTN1A1, PRR16, PCLO, PTPRD, FARP1, CDH2 and RAB27B. Functional genomics and fine-mapping pinpointed the potential causal variants, and expression quantitative trait loci analysis revealed the potential target genes regulated by the risk variants. Integrative analyses, including transcriptome-wide association study, proteome-wide association study and colocalization analyses, prioritized potential causal genes (including CTNND1 and RAB27B). Evidence from multiple analyses revealed possibly causal genes, including RAB27B, BTN3A2, PCLO and CTNND1. Finally, we showed that Ctnnd1 knockdown affected dendritic spine density and resulted in anxiety-like behaviours in mice, revealing the potential role of CTNND1 in anxiety disorders. Our study identified new risk loci, potential causal variants and genes for anxiety disorders, providing insights into the genetic architecture of anxiety disorders and potential therapeutic targets.