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Anxiety GWAS On Million Veteran Program Data Uncovers New Loci

NEW YORK – Using genetic and other data collected from the Million Veteran Program (MVP), investigators from Yale University, the Veterans Affairs Connecticut Healthcare Center, and elsewhere have tracked down a handful of loci that appear to influence susceptibility to anxiety disorder in European American and African American individuals.

As the team reported online today in the American Journal of Psychiatry, it brought together array-based genotyping data from almost 200,000 MVP participants for a genome-wide association study of generalized anxiety disorder. The work highlighted five anxiety-linked loci in individuals of European descent, including a chromosome 7 site near the MAD1L1 gene that was previously implicated in other conditions such as bipolar disorder and schizophrenia. It also revealed a distinct risk locus in African American individuals.

"Minorities are underrepresented in genetic studies, and the diversity of the Million Veteran Program was essential for this part of the project," co-first author Daniel Levey, a researcher at the VA Connecticut Healthcare Center and Yale University School of Medicine, said in a statement. "The genetic variant we identified occurs only in individuals of African ancestry, and would have been completely missed in less diverse cohorts."

For the study, Levey and his colleagued started with genotyping data for 241,541 European American and 61,796 African American participants in MVP, a VA Office of Research and Development-funded research project that includes veteran volunteers from across the US.

The researchers used more than 723,300 SNPs directly assessed with an Affymetrix Axiom array, imputed SNPs, performed quality control steps, and selected populations using reference data from the 1000 Genomes project.

For the main GWAS analyses, they searched for loci linked to anxiety — as measured with participant responses to a GAD-2 scale survey — in 175,163 European American participants and 24,448 African American participants.  

In the European American analysis, the team identified five loci with genome-wide significant associations with anxiety disorder, including several dozen SNPs at a chromosome 3 locus near the SATB1 and AS1 genes. An African American meta-analysis highlighted a single locus near a cation channel-related gene called TRPV6.

The results hinted at partial overlap between anxiety and other conditions, such as major depressive disorder. For example, at least one anxiety-associated SNP from the European-American analysis was associated with bipolar disorder or schizophrenia in previous GWAS. And when the authors applied a polygenic risk score developed from the MVP participants to data from prior GWAS of depression, post-traumatic stress disorder, or neuroticism, they saw still further overlap among risk SNPs.

When they looked at a secondary analysis focused on parts of the genome with potential ties to self-reported anxiety or panic disorder diagnoses, meanwhile, the researchers tracked down two loci with genome-wide significant associations to anxiety or panic disorder in the individuals of European descent, but none in African Americans.

Together, the authors suggested, the results provide additional evidence for genetic overlap between anxiety and other conditions that tend to co-occur with it, while uncovering potential targets to explore when developing future treatments.  

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