Identification of Novel Genomic Loci for Anxiety and Extensive Genetic Overlap with Psychiatric Disorders

BACKGROUND: Anxiety disorders are prevalent and anxiety symptoms often co-occur with psychiatric disorders. Here, we aimed to identify genomic risk loci associated with anxiety, characterize its genetic architecture, and genetic overlap with psychiatric disorders. METHODS: We used the largest available GWAS of anxiety (GAD-2 score), schizophrenia, bipolar disorder, major depression, and attention deficit hyperactivity disorder (ADHD). We employed MiXeR and LAVA to characterize the genetic architecture and genetic overlap between the phenotypes. Additionally, conditional and conjunctional false discovery rate analyses were performed to boost the identification of genomic loci associated with anxiety and those shared with psychiatric disorders. Gene annotation and gene set analyses were carried out using OpenTargets and FUMA, respectively. RESULTS: Anxiety was polygenic with 8.4k estimated genetic risk variants and overlapped extensively with psychiatric disorders (4.1–7.8k variants). Both MiXeR and LAVA revealed predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 154 anxiety loci (139 novel) by conditioning on the psychiatric disorders. We identified loci shared between anxiety and major depression (n = 66), bipolar disorder (n = 19), schizophrenia (n = 51), and ADHD (n = 37). Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways and differential tissue expression in more diverse tissues than those annotated to the shared loci. CONCLUSIONS: Anxiety is a highly polygenic phenotype with extensive genetic overlap with psychiatric disorders. These genetic overlaps enabled the identification of novel loci for anxiety and shared loci with psychiatric disorders. The shared genetic architecture may underlie the comorbidity of anxiety, and the identified genetic loci implicate molecular pathways that could become potential drug targets.