Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study

Abstract

We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups. Through ancestry-specific and cross-ancestry genome-wide association studies, we identified 51 anxiety-associated loci, 39 of which were novel. In addition, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, admixed American and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex and brain stem. Transcriptome-wide and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. Anxiety also showed global and local genetic correlations with depression, schizophrenia and bipolar disorder and widespread pleiotropy with several physical health domains. Overall, this study expands our knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information.

Figure 1.

Genetic correlations among anxiety phenotypes assessed in participants of European descent. The cohorts investigated include All of Us Research Program (AoU), FinnGen Study, Million Veteran Program (MVP), Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Psychiatric Genomics Consortium (PGC), and UK Biobank (UKB). The analysis was conducted using linkage score regression approach. Full statistics are reported in Supplemental Table 1.

Figure 2.

Genomic structural equation modeling applied to anxiety phenotypes assessed in individuals of European descent. Factor loadings and model fit for the confirmatory factor analysis model of the common anxiety factor (ANX) are reported. The cohorts investigated include All of Us Research Program (AoU), FinnGen Study, Million Veteran Program (MVP), Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Psychiatric Genomics Consortium (PGC), and UK Biobank (UKB).

Figure 3.

Manhattan plots of genome-wide, transcriptome-wide, and proteome-wide association statistics (bottom, center, and top, respectively) related to the common anxiety factor (ANX). Transcriptome-wide data are those obtained from the multiple-tissue analysis (Supplemental Table 10). Y-axis refers to -log₁₀(p-value) obtained from two-sided statistical tests. Dashed lines represent Bonferroni multiple testing correction applied in each analysis. The labeled genes are those with convergent evidence across analyses.

Figure 4.

Within-ancestry and cross-ancestry polygenic risk score (PRS) associations of the common anxiety factor (ANX). Odds ratios (OR) and corresponding 95% confidence intervals (95%CI) are reported. Full statistics including two-sided p-values are available in Supplemental Table 4. In the within-ancestry, the EUR-ANX PRS (excluding EUR AoU from the training sample, effective N=468,611) is tested against the EUR AoU sample (effective N=61,153). In the cross-ancestry analysis, EUR-ANX PRS (with EUR AoU in the training sample, effective N=529,764) is tested against AoU samples of African (AFR, effective N=17,799), Admixed-American (AMR, effective N=14,741), East Asian (EAS, effective N=1,259), and South Asian (SAS, effective N=499) descent.

Figure 5

A. Venn diagrams of unique and shared causal variants showing polygenic overlap (gray) of the common anxiety factor (ANX) with major depressive disorder (MDD), bipolar disorder (BIP), and schizophrenia (SCZ). The numbers indicate the estimates of causal variants and their standard errors (in thousands), explaining 90% of the SNP heritability in each phenotype. The size of the circles reflects the degree of polygenicity. B. Chord diagram representing ANX local genetic correlations with respect to attention deficit and hyperactivity disorder (ADHD), BIP, MDD, post-traumatic stress disorder (PTSD), and SCZ.

Figure 6.

Phenome-wide genetic correlation of the common anxiety factor. The x-axis reports the genetic correlation of ANX with traits available from UK Biobank, FinnGen, and Million Veteran Program. Y-axis refers to −log₁₀(p-value) obtained from two-sided statistical tests. Bonferroni-significant results are color-coded based on the corresponding categories. Full statistics of the Bonferroni-significant results are available in Supplemental Table 18. Non-significant results are reported in grey.