The largest study ever conducted on genetic risk factors for anxiety, a genome-wide association study (GWAS) of 200,000 participants recently published in the American Journal of Psychiatry, found significant associations between self-reported anxiety and specific single nucleotide polymorphisms (SNPs).

Daniel Levey, PhD, from the department of psychiatry, Yale University School of Medicine, New Haven, Connecticut, and colleagues pulled data from one of the largest biobanks in the world, the Million Veteran Program. To assess anxiety and related disorders, researchers used the Generalized Anxiety Disorder 2-item scale (GAD-2), as well as self-reported physician diagnosis of an anxiety disorder. The study sample included individuals from European and African American backgrounds. In addition, the researchers carried out a conditional analysis for depression, given high rates of comorbidity between anxiety and depressive disorders.

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The investigators found 5 specific genome-wide significant loci for European Americans (near SATB1, ESR1, LINC01360/LRRIQ3, MAD1L1, and TCEA2/OPRL1) and 1 locus for African Americans (near TRPV6) based on GAD-2 scores. In multitrait-based conditional and joint analyses, SATB1, on chromosome 3, and ESR1, on chromosome 6, remained genome-wide significant. The researchers partially replicated the findings based on other previously published GWAS data.

SNP heritability for anxiety ranged from 5.58% to 8.79% for GAD-2 and physician diagnosis of anxiety, respectively. Furthermore, depressive symptoms (P =1.95×10−53) and neuroticism (P =6.53×10−53) were genetically correlated with GAD-2 scores. In an analysis of polygenic risk scores, the researchers identified significant overlap between anxiety and major depressive disorder (variance explained, 0.24%) as well as PTSD (variance explained, 0.23%).


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A global regulator of gene expression involved in neuronal development, SATB1 modulates corticotropin-releasing hormone (CRH). Corticotropin plays an essential role in the hypothalamic-pituitary-adrenal axis, which influences stress, anxiety, and fear responses to stimuli. Earlier animal models have proposed the CRH receptor 1 (CRHR1) gene as a target for treating anxiety based on anxiolytic effects of CRHR1 antagonists in animal studies. Patients’ variations in CRHR1, however, may limit the efficacy of CRHR1 antagonists and other glucocorticoid-targeted therapeutic agents.

Genetic variants in the estrogen receptor ESR1 also account for sex differences in the frequency and severity of anxiety and PTSD, which are more common in women than in men. One significant limitation of the study was the relatively small number of female participants — a mere 7.5% of the Million Veteran Program participants — especially given the findings on ESR1.

Nevertheless, the study’s authors emphasize that its findings demonstrate genetic risk factors that account for the overlap between anxiety, PTSD, and neuroticism. The investigators noted that their research “provides additional genetic evidence for the overlap between disorders that are frequently comorbid with anxiety,” potentially offering novel therapeutic pathways.

Reference

Levey DF, Gelernter J, Polimanti R, et al. Reproducible risk loci and psychiatric comorbidities in anxiety: results from ~ 200,000 Million Veteran Program participants [published online January 7, 2020]. Am J Psychiatry. doi:10.1176/appi.ajp.2019.19030256.