The largest-to-date study relating DNA variations and anxiety disorders has revealed several previously unidentified locations in the human genome where variations in the sequence tend to occur in people with anxiety, compared with people who don't have anxiety.

The findings provide new insights into genetic risk mechanisms and biological processes that underpin anxiety. The study, a genome-wide association study or GWAS, also replicates past findings suggesting genetic linkages between anxiety and major depressive disorder, PTSD, bipolar disorder, and neuroticism. (Neuroticism is a broad behavioral trait marked by feelings that may include anxiety, worry, fear, anger, envy, jealousy, guilt, depression, and loneliness.)

A team whose leaders included Daniel F. Levey, Ph.D., a 2019 BBRF Young Investigator; Joel Gelernter, M.D.; and Murray Stein M.D., MPH, noted in their findings, published in the American Journal of Psychiatry, that while analysis of genome information has advanced rapidly in many disease areas, "understanding of the genetics of anxiety disorders has lagged." This is concerning in part because annually, 1 in 10 Americans suffers from an anxiety disorder (it's the most prevalent psychiatric diagnosis), and statistics indicate that only about 1 in 3 of those affected ever receive treatment.

Trying to find statistically significant linkages between DNA variations in the 3 billion-"letter" human genome and a complex trait such as anxiety is difficult. One reason is that like other complex traits (depression or schizophrenia, for example), anxiety is thought to be associated with as many as hundreds of thousands of distinct DNA variations that occur commonly in the human population.

Each anxiety-linked variation, when considered alone, has a small effect on risk for the disorder. Different numbers and combinations of such variants likely have to be present in an individual—possibly in combination with environmental factors such as chronic stress or trauma—to produce genetic risk above the level of risk in the general population.

The size of the sample is critical in generating meaningful results in GWAS studies. In the study just reported, data on over 199,000 contributors to the Million Veteran Program (MVP) biobank administered by the U.S. Department of Veterans Affairs were used to perform the genetic analysis. This sample is many times the size of samples previously used in past anxiety GWAS studies.

The researchers found novel genetic variants in and around the locations of several genes, some of which have previously been linked to anxiety based on the functions they are thought to perform.

In broad terms, the findings showed "significant genetic overlap" between anxiety and conditions including PTSD and depression that frequently co-occur with anxiety. This fact, the researchers said, "provides biological evidence that this known clinical comorbidity is due at least in part to shared genetic etiology [causation]." The team found strong positive correlations genetically between participants with recent anxiety symptoms and depressive symptoms and/or neuroticism.

In the portion of the combined sample that is of European ancestry, the strongest GWAS correlation with anxiety was a gene called SATB1, which is thought to influence the activity ("expression") of multiple other genes involved in neuronal development. One such "influenced" gene is called CRH, which encodes the Corticotropin Releasing Hormone, a protein that plays a central role in the operation of the body's HPA axis, the linked system in which the hypothalamus, pituitary, and adrenal glands modulate stress and the fear/anxiety response. The protein product of a gene called CRHR1, the researchers note, has been a proposed treatment target for anxiety and stress-related disorders.

Another strong correlation in the European ancestry portion of the sample was between anxiety and a gene called ESR1, which encodes one of several cellular receptors for estrogen. It has been a focus in animal models of anxiety-like behaviors. Although estrogen is important in both sexes, the researchers say that their finding of an association between ESR1 and anxiety "may have implications for our understanding of sex differences in anxiety disorders and stressor-related disorders like PTSD," which occur more frequently in females.

For this reason, among others, the researchers say, future genetic analyses should include substantially more women in order to forge more substantial linkages between anxiety and variations in ESR1 and other genes that may be relevant to sex disparities in incidence and comparative risk. Future samples also would ideally include many more people of non-European heritage. The current study found a novel DNA risk variant that occurs almost exclusively in people of African descent. The variant, in the gene TRPV6, encodes a protein involved in calcium-ion transport.

The research team also included: Patrick F. Sullivan, M.D., 2014 BBRF Lieber Prize winner and 2010 Distinguished Investigator; Renato Polimanti, Ph.D., 2015 BBRF Young Investigator; and Hang Zhou, Ph.D., 2018 BBRF Young Investigator.