Veteran study details genetic basis for anxiety, links anxiety and depression

Summary: A large genome-wide study of over 200,000 veterans reveals six genetic variants linked to anxiety. Some of the variants have previously been linked to risk factors for PTSD, schizophrenia, and bipolar disorder. The findings provide the first convincing molecular explanation for the link between depression and anxiety.

Source: Yale

A massive genomewide analysis of approximately 200,000 military veterans has identified six genetic variants linked to anxiety, researchers from Yale and colleagues at other institutions report Jan. 7 in the American Journal of Psychiatry.

Some of the variants associated with anxiety had previously been implicated as risk factors for bipolar disorder, posttraumatic stress disorder, and schizophrenia.

The new study further contributes to 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, 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, 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 found only in African Americans.

“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, San Diego VA staff psychiatrist and Distinguished Professor of Psychiatry and of family medicine and public health at UCSD.

Some 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.

This shows a depressed looking woman
The new study further contributes the first convincing molecular explanation for why anxiety and depression often coexist. Image is in the public domain.

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, posttraumatic stress disorder, 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 Yale’s Daniel Levey, a postdoctoral associate and co-lead author of the study.

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

Said Gelernter, “This is a rich vein we have just begun to tap.”

About this neuroscience research article

Media Contacts:
Bess Connolly – Yale
Image Source:
The image is in the public domain.

Original Research: Closed access
“Reproducible Genetic Risk Loci for Anxiety: Results From ∼200,000 Participants in the Million Veteran Program”. Murray Stein et al.
American Journal of Psychiatry doi:10.1176/appi.ajp.2019.19030256.


Reproducible Genetic Risk Loci for Anxiety: Results From ∼200,000 Participants in the Million Veteran Program

Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder.

Using one of the world’s largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis.


The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75).

This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.

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