NEW YORK – New research on diverse human populations has significantly expanded the suite of genetic variants implicated in anxiety disorders. Some of these variants appear to influence gene and protein activity in specific brain tissues.
"Our multiomics analyses identified novel pathways putatively involved in the pathogenesis of anxiety and refined plausible mechanisms related to previously reported loci," corresponding author Renato Polimanti, a researcher at the Yale University School of Medicine and School of Public Health, and his colleagues wrote in a paper published in Nature Genetics on Wednesday.
For their study, the investigators performed genome-wide association studies and a GWAS meta-analysis on data from 97,383 patients with anxiety and almost 1.1 million unaffected controls from the All of Us Research Program, the Lundbeck Foundation Initiative for Integrative Psychiatric Research, FinnGen, the Million Veteran Program (MVP), the UK Biobank (UKB) project, and the Psychiatric Genomics Consortium.
The participants included nearly 1.1 million individuals of European ancestry, 118,071 of African ancestry, 10,534 of South Asian descent, 5,083 of East Asian ancestry, and 36,634 admixed Americans.
"Studying these cohorts, we identified multiple loci associated with anxiety and gained insights into the roles of polygenic risk, pleiotropy, tissue-specific regulation, and transcriptomic and proteomic variations in the pathogenesis of anxiety disorders," the authors reported.
With their ancestry-specific GWAS, meta-analyses, and cross-ancestry GWAS, the researchers unearthed 39 new and a dozen already known anxiety-associated loci. Using the fine-mapping tool PAINTOR, meanwhile, they saw potential regulatory roles in brain regions for some of the variants found in European or African ancestry groups.
The team also put together polygenic risk scores (PRS) for anxiety disorder-associated variants in the European ancestry participants that appeared to track with anxiety phenotypes in the African, admixed American, and East Asian ancestry groups. The South Asian group appeared to have an effective sample size that was too small to find similar PRS overlap.
In their subsequent transcriptome-wide association study, which focused on 13 brain tissue types profiled in version 8 of the GTEx database, the investigators found 152 significant associations involving 39 genes. Meanwhile, a TWAS that included additional GTEx tissues outside of the brain led to 94 loci regulating anxiety disorder-associated transcripts.
All told, the researchers explained, their TWAS and proteomic analyses linked 115 genes to anxiety disorders, which may enable a better understanding of the conditions and biologically informed treatment strategies.
Their analyses uncovered genes with tissue-specific ties to anxiety disorders — such as the dopamine receptor-coding gene DRD2, which appeared to have specific effects in the cerebellum — along with genes affecting various tissue types.
Finally, the team's phenome-wide correlation analyses suggested that genetic contributors to anxiety disorders tend to track with those involved in more than 1,900 other phenotypes, including mental health-related traits or conditions, based on data spanning nearly 11,200 distinct phenotypes in participants from the UKB, MVP, and FinnGen efforts.
Together, "this large-scale genome-wide and multiomics investigation yielded new insights into the biology of anxiety disorders," the authors wrote.