Open AccessGenome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program
Author(s) -
Murray B. Stein,
Daniel F. Levey,
Zhongshan Cheng,
Frank R. Wendt,
Kelly Harrington,
Gita A. Pathak,
Kelly Cho,
Rachel Quaden,
Krishnan Radhakrishnan,
Matthew J. Girgenti,
YukLam Ho,
Daniel Posner,
Mihaela Aslan,
Ronald S. Duman,
Hongyu Zhao,
VA Million Veteran Program,
Renato Polimanti,
John Concato,
Joel Gelernter
Publication year - 2021
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-020-00767-x
Subject(s) - neuroticism , heritability , genome wide association study , missing heritability problem , anxiety , mood , biology , genetic association , traumatic stress , major depressive disorder , clinical psychology , genetics , psychiatry , psychology , personality , genotype , gene , single nucleotide polymorphism , social psychology
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.