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

Abstract

We conducted genome-wide association analyses in over 250,000 participants of European and African ancestry from the Million Veteran Program using electronic health record-validated posttraumatic 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.

The Validity of Brief Phenotyping in Population Biobanks for Psychiatric Genome-Wide Association Studies on the Biobank Scale

“…Multivariate methods for GWAS built around genetic correlations [32] offer promise for distinguishing the shared and specific genetic influences on psychiatric symptoms. This has already been demonstrated for genetic influences on distinct symptoms of PTSD [34]. Using data from 186,689 participants of the Million Veteran Program, shared and distinct genetic associations with the reexperiencing, avoidance, and hyperarousal symptoms of PTSD were observed, as well as genetic associations with overall PTSD symptoms and diagnosis.…”

“…Using data from 186,689 participants of the Million Veteran Program, shared and distinct genetic associations with the reexperiencing, avoidance, and hyperarousal symptoms of PTSD were observed, as well as genetic associations with overall PTSD symptoms and diagnosis. Furthermore, PTSD symptoms were separable from internalizing traits and disorders (anxiety disorders, depression, and neuroticism), and what shared genetic component was present appeared to act via hy-DOI: 10.1159/000516837 perarousal symptoms, rather than via reexperiencing or avoidance [34]. Biobanks therefore offer the potential for robust investigation of psychiatric illness at the symptom level.…”

Gene Expression Analysis in Three Posttraumatic Stress Disorder Cohorts Implicates Inflammation and Innate Immunity Pathways and Uncovers Shared Genetic Risk With Major Depressive Disorder

“…Recently, UBA7 was implicated in a transcriptome-wide association study (TWAS) of PTSD using brain tissue ( Girgenti et al, 2021 ), confirming the association we observe in whole blood. The summary statistics utilized in Girgenti et al were obtained from MVP ( Stein et al, 2021 ) as opposed to the current study, which used summary statistics from PGC-PTSD (Maihofer et al, submitted), demonstrating an independent replication of the UBA7 finding. We also identified two eQTLs involving major histocompatibility complex (MHC) genes, HLA-F and HSPA1B , that displayed evidence for a shared genetic effect with MDD GWAS variants.…”

“…Even with large sample sizes, it has been difficult to identify robust regions of association with PTSD, illustrating the complex and multi-genic nature of the disorder. Recent GWAS reports from the PGC-PTSD and Million Veteran Program (MVP) have had greater success in identifying PTSD-associated loci when utilizing quantitative symptom severity and symptom subdomains instead of PTSD diagnosis (Maihofer et al, submitted; Stein et al, 2021 ). Nonetheless, the biological mechanisms underlying these largely non-coding regions of association have not yet been elucidated.…”

Using Monozygotic Twins to Dissect Common Genes in Posttraumatic Stress Disorder and Migraine

“…We investigated 60 PTSD candidate genes that had been previously reported to be associated with PTSD in different studies ( Cornelis et al, 2010 ; Almli et al, 2014 ; Mehta et al, 2019 ; Bian et al, 2020 ; Stein et al, 2021 ), including genes uncovered in a GWAS of over 250,000 participants in the Million Veteran Program ( Stein et al, 2021 ). For these 60 candidate genes, there were 4411 CpGs detected in the current study on the EPIC microarray that could be tested.…”