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Study of 200,000 Vets Identifies Six Gene Variants Linked to Anxiety and One Is Found Only in African Americans; Study Highlights Advantages of Scale & Diversity in Association Studies; Evidence Also Found for Frequent Co-Morbidity of Anxiety & Depression

A massive genome-wide analysis of approximately 200,000 military veterans has identified six genetic variants linked to anxiety, researchers from Yale and colleagues at other institutions report in an article published online on January 7, 2020, in the American Journal of Psychiatry (https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2019.19030256). The article is titled “Reproducible Genetic Risk Loci for Anxiety: Results from ∼200,000 Participants in the Million Veteran Program.” Some of the variants associated with anxiety had previously been implicated as risk factors for bipolar disorder, post-traumatic stress disorder (PTSD), and schizophrenia. The new study further contributes the first convincing molecular explanation for why anxiety and depression often coexist. "This is the richest set of results for the genetic basis of anxiety to date," said co-lead author Joel Gelernter, MD, the Foundations Fund Professor of Psychiatry, Professor of Genetics and of Neuroscience at Yale. "There has been no explanation for the comorbidity of anxiety and depression and other mental health disorders, but here we have found specific, shared genetic risks." Finding the genetic underpinnings of mental health disorders is the primary goal of the Million Veteran Program (MVP), a compilation of health and genetic data on U.S. military veterans run by the U.S. Veterans Administration. The research team analyzed the program's data and zeroed in on six variants linked to anxiety. Five were found in European Americans and one was found only in African Americans. The findings for the African American participants are especially important, says Dr. Dan Levey, PhD, of the VA Connecticut Healthcare Center and Yale University, and a co-lead author of the study. "Minorities are underrepresented in genetic studies, and the diversity of the Million Veteran Program was essential for this part of the project. The genetic variant we identified occurs only in individuals of African ancestry, and would have been completely missed in less diverse cohorts." The study produced the first genome-wide significant findings on anxiety in African ancestry, noted Dr. Levey. Approximately 18% of MVP participants are African American.

As noted above, the anxiety-related genome locations also show overlap with other psychiatric conditions. One of the identified locations has previously been linked with risk for bipolar disorder and schizophrenia. The study also shows genetic overlap between anxiety symptoms and depression, PTSD (which is related to anxiety), and neuroticism--a personality trait that has been shown to increase risk for anxiety and related disorders. The results support the idea that overlap with these other traits is at least partially due to a significant genetic commonality, according to the researchers.

"While there have been many studies on the genetic basis of depression, far fewer have looked for variants linked to anxiety, disorders of which afflict as many as 1 in 10 Americans," said senior author Murray Stein, MD, MPH, San Diego VA Staff Psychiatrist and Distinguished Professor of Psychiatry and of Family Medicine and Public Health at the University of California-San Diego (UCSD).

Some of the six variants were linked to genes that help govern gene activity or, intriguingly, to a gene involved in the functioning of receptors for the sex hormone estrogen. While this finding might help explain why women are more than twice as likely as men to suffer from anxiety disorders, researchers stressed that the variant affecting estrogen receptors was identified in a veteran cohort made up mostly of men, and said further investigation is necessary.

Another of the newly discovered anxiety gene variants, MAD1L1, whose function is not fully understood, was also highly notable. Variants of this gene have already been linked to bipolar disorder, PTSD, and schizophrenia.

"One of the goals of this research is to find important risk genes that are associated with risk for many psychiatric and behavioral traits for which we don't have a good explanation," said Dr Levey

To do the study, Yale's researchers teamed up with colleagues at the Veteran Affairs Connecticut Healthcare System, the VA San Diego Healthcare System, and the University of California San Diego.

Said Dr. Gelernter, "This is a rich vein we have just begun to tap."

MVP is a national, voluntary research program funded by VA's Office of Research and Development. It is one of the world's largest databases of health and genomic information. MVP partners with veterans receiving care in VA to study how genes affect health. As of November 2019, MVP had enrolled more than 800,000 veterans.

"MVP has enormous potential for increasing our knowledge about the genetics underlying a huge range of traits, including psychiatric traits. It is one of the best samples in the world for this purpose," said Dr. Gelernter.

For more information on MVP, visit http://www.research.va.gov/MVP.

[Yale press release] [VA press release] [Million Veteran Program (MVP)] [American Journal of Psychiatry abstract]