Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program

• Published in: Nature genetics Vol. 53; no. 2; pp. 174 - 184
• Main Authors: Stein, Murray B., Levey, Daniel F., Cheng, Zhongshan, Wendt, Frank R., Harrington, Kelly, Pathak, Gita A., Cho, Kelly, Quaden, Rachel, Radhakrishnan, Krishnan, Girgenti, Matthew J., Ho, Yuk-Lam Anne, Posner, Daniel, Aslan, Mihaela, Duman, Ronald S., Zhao, Hongyu, Polimanti, Renato, Concato, John, Gelernter, Joel
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-02-2021; Nature Publishing Group
• Subjects: 45; 45/43; 631/477; 692/308/2056; 692/699/476; Agriculture; Animal Genetics and Genomics; Anxiety; Anxiety Disorders - genetics; Biological effects; Biomedical and Life Sciences; Biomedicine; Black or African American - genetics; Brain; Cancer Research; Case-Control Studies; Comorbidity; Drug Repositioning; Electronic health records; Electronic medical records; Gene expression; Gene Function; Genetic aspects; Genetic diversity; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotype & phenotype; Health aspects; Heritability; Human Genetics; Humans; Linkage Disequilibrium; Loci; Mental depression; Mental disorders; Mental Disorders - genetics; Meta-analysis; Mood; Multivariate statistical analysis; Neurosis; Phenotypes; Polymorphism, Single Nucleotide; Post traumatic stress disorder; Psychological aspects; Psychological stress; Regression analysis; Stress Disorders, Post-Traumatic - etiology; Stress Disorders, Post-Traumatic - genetics; United States; Veterans; White People; United States
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-020-00767-x

We conducted genome-wide association analyses of over 250,000 participants of European (EUR) and African (AFR) ancestry from the Million Veteran Program using electronic health record-validated post-traumatic stress disorder (PTSD) diagnosis and quantitative symptom phenotypes. Applying genome-wide multiple testing correction, we identified three significant loci in European case-control analyses and 15 loci in quantitative symptom analyses. Genomic structural equation modeling indicated tight coherence of a PTSD symptom factor that shares genetic variance with a distinct internalizing (mood–anxiety–neuroticism) factor. Partitioned heritability indicated enrichment in several cortical and subcortical regions, and imputed genetically regulated gene expression in these regions was used to identify potential drug repositioning candidates. These results validate the biological coherence of the PTSD syndrome, inform its relationship to comorbid anxiety and depressive disorders and provide new considerations for treatment.
Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in individuals of European and African ancestry provide insights into its relationship with anxiety and depressive disorders and identify potential candidates for drug repositioning.