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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 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.

SUBMITTER: Stein MB

PROVIDER: S-EPMC7972521 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Stein Murray B MB Levey Daniel F DF Cheng Zhongshan Z Wendt Frank R FR Harrington Kelly K Pathak Gita A GA Cho Kelly K Quaden Rachel R Radhakrishnan Krishnan K Girgenti Matthew J MJ Ho Yuk-Lam Anne YA Posner Daniel D Aslan Mihaela M Duman Ronald S RS Zhao Hongyu H Polimanti Renato R Concato John J Gelernter Joel J

Nature genetics 20210128 2

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 c ...[more]

PMID: 33510476

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Project description:ObjectiveTo examine the spectrum and severity of cognitive symptoms in veterans with migraine, traumatic brain injury (TBI), or both; and to evaluate the extent to which psychiatric conditions contribute to the relationship of migraine and TBI with cognitive symptoms.BackgroundMigraine contributes significantly to global disability, with veterans facing additional burdens due to high comorbidity of TBI and psychiatric conditions. Understanding the intersection of these conditions is crucial for improving veterans' health-care outcomes.MethodsThis observational study used self-reported data from 338,217 veterans enrolled in the Million Veteran Program (MVP) to assess cognitive symptoms using the Medical Outcomes Study Cognitive Functioning Scale Revised (MOS-Cog-R) and psychiatric conditions in veterans with migraine only, TBI only, both, or neither.ResultsOf the participants, 30,080/338,217 (8.9%) veterans reported migraine, 31,906/338,217 (9.4%) reported TBI, and 7828/338,217 (2.3%) reported both migraine and TBI. Veterans with only migraine or only TBI reported similar levels of cognitive symptoms (M = 74.19, standard deviation [SD] = 25.18; M = 73.87, SD = 24.98, respectively), which were substantially higher than veterans without these conditions (M = 62.52, SD = 27.90). Veterans with both conditions reported the most cognitive symptoms (M = 83.01, SD = 22.13) and psychiatric conditions (depression = 5041/7828 [64.4%], anxiety = 3735/7828 [47.7%], post-traumatic stress disorder = 4243/7828 [54.2%]). The association of migraine and TBI with cognitive symptoms persisted beyond the influence of psychiatric conditions (B = -2.20, standard error = -0.36, p < 0.001).ConclusionVeterans with migraine reported cognitive challenges analogous to veterans with TBI, indicating a need for careful attention to cognitive symptoms in veterans with migraine. Further, the associations of migraine and TBI with cognitive symptoms in veterans were not explained by psychiatric conditions. These findings encourage future research to elucidate the association between self-reported and objective cognitive symptoms and to identify factors, including environmental exposure and genetic influences, contributing to cognitive impairment to optimize the assessment and treatment of veterans with migraine.

Project description:BackgroundGenetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program.MethodsAn ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization.ResultsThe discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality.ConclusionA set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality.

Project description:PurposePrimary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).DesignCross-sectional study.ParticipantsMVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.MethodsWe tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.Main outcome measuresPerformance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.ResultsGRS were significantly associated with POAG (P < 5 × 10-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.ConclusionsVaried performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

Project description:BackgroundHeight has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.Methods and findingsAnalyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.ConclusionsWe conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.

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

Publications

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

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