Anxiety's Genetic Roots Revealed

Megan Brooks

January 08, 2020

The largest genetics study on anxiety to date has uncovered six novel gene variants associated with the disorder, in findings that may point to new treatment targets.

The results also suggest there is significant genetic overlap between anxiety, major depressive disorder (MDD), and other psychiatric disorders that are often comorbid with anxiety.

"This is the richest set of results for the genetic basis of anxiety to date," co-lead author Joel Gelernter, MD, of Yale University School of Medicine, New Haven, Connecticut, said in a release.

"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," Gelernter added.

The results were published online January 7 in the American Journal of Psychiatry.

Six Novel Variants

The genome-wide association study used genotyping data for 241,541 European American and 61,796 African American participants in the Veterans Affairs' Million Veteran Program, one of the largest biobanks that includes genetic, environmental, and medical information.

The researchers identified six risk loci with genome-wide significant association to anxiety disorder — five in European Americans and one in African Americans.

These genes play roles in the hypothalamic-pituitary-adrenal (HPA) axis, neuronal development, and global regulation of gene expression.

The single significant result in African Americans is an insertion variant near the transient receptor potential cation channel subfamily V member 6 (TRPV6) locus that is rare outside of African ancestry.

"This highlights the importance of studying genetic risks in diverse populations — otherwise these signals may be missed entirely," the investigators note.

In European Americans, the two strongest anxiety-related loci were on chromosome 3 near special AT-rich sequence-binding protein-1 (SATB1), a global regulator of gene expression that influences expression of multiple genes involved neuronal development, and on chromosome 6 near estrogen receptor alpha (ESR1), which encodes an estrogen receptor.

While this finding might help explain why women are more than twice as likely as men to suffer from anxiety, the researchers note that they identified the variant affecting estrogen receptors in a veteran cohort made up mostly of men, and that further investigation is needed.

In European Americans, the researchers identified a risk locus on chromosome 7 near the mitotic checkpoint gene MAD1L1, which was previously identified in genome-wide association studies of bipolar disorder and schizophrenia. This suggests it may have genetic vulnerability across several psychiatric disorders.

They also found "very strong" genetic correlation between anxiety and psychiatric traits such as depression and neuroticism but relatively weaker genetic overlap with neurological disorders.

Anxiety, Depression Tightly Connected

Commenting on the findings for Medscape Medical News, James Potash, MD, MPH, psychiatrist-in-chief, Johns Hopkins Medicine, in Baltimore, Maryland, said the results "confirm that genetic susceptibility to depression and to anxiety are very tightly connected. That's not a surprise, but reassuring, and helps tell us we are on the right path."

In terms of the genes and gene pathways, Potash said it's encouraging to see one of the key genes in the HPA axis — the corticotropin-releasing hormone receptor 1 is implicated in anxiety.

"This is one of the pathways that we've long known plays a role in anxiety and an important role in response to stress," he noted.

The other "intriguing" finding, said Potash, is the association between ESR1 and anxiety "in a study that is almost all men. That tells us it's a more complicated picture than just being about female hormones," he noted.

Potash said a "major hope" from this type of research is that it reveals particular genes or gene pathways that "tell you something about how anxiety is unfolding in the brain and points you in the direction of potential new targets for new medications." Genetic information may also aid in diagnosis and predicting prognosis and response to treatment.

Funding for the study was provided by grants from the Veterans Affairs Office of Research and Development and VA Cooperative Studies Program. Gelernter is named as co-inventor on a patent application for genotype-guided dosing of opioid agonists. Potash has disclosed no relevant financial relationships.

Am J Psychiatry. Published online January 7, 2020. Abstract

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