Genomics of posttraumatic stress disorder in veterans: Methods and rationale for Veterans Affairs Cooperative Study #575B

Abstract

Objectives Heritability in the risk for developing posttraumatic stress disorder (PTSD) has been established, but most genome‐wide association studies (GWASs) of PTSD involve relatively small sample sizes and limited identification of associated genetic loci. This report describes the methodology of a Veterans Affairs (VA) Cooperative Studies Program GWAS of PTSD among combat‐exposed U.S. veterans. Methods Probable cases (with PTSD) and probable controls (without PTSD) were identified from among veterans enrolled in the VA Million Veteran Program (MVP) with an algorithm developed using questionnaire responses and electronic health record information. This algorithm, based on a statistical model, relied on medical chart reviews as a reference standard and was refined using telephone interviews. Subsequently, to evaluate the impact of probabilistic phenotyping on statistical power, the threshold probability for case–control selection was varied in simulations. Results As of September 2018, >695,000 veterans have enrolled in MVP. For current analyses, genotyping data were available for >353,000 participants, including >83,000 combat‐exposed veterans. A threshold probability of 0.7 for case and control designation yielded an interim >16,000 cases and >33,000 controls. Conclusions A formal methodological approach was used to identify cases and controls for subsequent GWAS analyses to identify genetic risk loci for PTSD.

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

“…We first performed GWAS of PTSD in American veterans of European (EUR) and African (AFR) ancestry, basing diagnosis on a validated VA EHR algorithm 23 that had excellent discriminative ability for lifetime PTSD cases vs. controls as determined by chart review (0.90 sensitivity, 0.97 specificity, 0.87 positive predictive value, and 0.90 negative predictive value), and substantial agreement with gold-standard Clinician-Administered PTSD Scale (CAPS) interview (90.2% agreement and κ = 0.75 (95% CI: 0.62, 0.88)) 17 . GWAS analyses were carried out (on two tranches of data genotyped on the same array platform at two different times) on SNP dosages imputed from 1000 Genomes Phase 3 using logistic regression for case-control traits and linear regression for continuous traits in PLINK 2.0 24 , separately by ancestry, adjusting for age, sex, and the first 10 principal components of ancestry.…”

“…The use of biobanks with relatively large numbers of PTSD cases offers the opportunity to provide unprecedented sample size and, importantly, uniformity of phenotypic and genotypic platforms 17 . This investigation was conducted within the US Veterans Affairs Million Veteran Program (MVP) 18 and included several PTSD phenotypic definitions: a validated, algorithmically-defined case-control definition using data from the electronic health record (EHR), which was subsequently meta-analyzed with the case-control PGC-PTSD GWAS 13 ; and quantitative trait definitions encompassing PTSD subdomains based on recent self-reported symptoms: re-experiencing (in an expanded sample from that previously reported 16 ), avoidance, hyperarousal, and a total index of recent symptom severity (PCL-Total).…”

Validation of an Electronic Medical Record–Based Algorithm for Identifying Posttraumatic Stress Disorder in U.S. Veterans

“…This study was undertaken as a part of a GWAS of PTSD, “Genomics of Posttraumatic Stress Disorder in Veterans” (VA Cooperative Study #575B; see Radhakrishnan et al., ), which is being conducted within the VA Million Veteran Program (MVP). The MVP, as a mega‐biobank established within the national VA healthcare system, collects blood specimens and questionnaires from consented veteran volunteers and links them with consent for EMR research use, as has been described in detail elsewhere (Gaziano et al., ).…”

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

“…Derived from the uniquely informative US Veterans Affairs MVP (Gaziano et al, 2016), our case-control sample was phenotyped using a validated algorithm applied to EHR data with exemplary diagnostic properties Radhakrishnan et al, 2019), enabling us to analyze data from over 250,000 genotyped veterans (including nearly 50,000 PTSD cases). Moreover, we were able to examine simultaneously genomewide associations with several other PTSD phenotypes reflecting various aspects of symptom type and severity, respectively.…”