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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.

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Fig. 1: Manhattan plots for MVP case-control GWAS and MVP/PGC GWAS meta-analysis in EUR samples.
Fig. 2: GWS findings, by ancestry and PTSD phenotype.
Fig. 3: Phenotypic and genetic correlations between case-control, PCL-Total and subscale scores.
Fig. 4: LDSC genetic correlation analyses in EUR showing traits from UK Biobank and PGC psychiatric disorders.
Fig. 5: Genetic relationship between PCL-Total and other mental health phenotypes.
Fig. 6: GenomicSEM model with confirmatory factor analysis indicating two correlated factors.
Fig. 7: Genetically regulated transcriptomic changes with PCL-Total (n = 186,689).

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Data availability

The GWAS summary statistics generated and/or analyzed during the current study will be made available via dbGAP; the dbGaP accession assigned to the MVP is phs001672.v1.p. The website is https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v1.p1.

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Acknowledgements

This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration and was supported by funding from the VA Cooperative Studies Program (CSP, no. CSP575B) and the Veterans Affairs Office of Research and Development MVP (grant nos. MVP000 and VA Merit MVP025). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. We thank the veterans who participated in this study, and the members of the VA CSP and MVP study teams, without whom this work would not have been possible.

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M.B.S. and J.G. had primary responsibility for design of the study. M.B.S., J.G., J.C., K.R. and M.A. supervised the study and managed and organized the group. D.F.L., Z.C., F.R.W., G.A.P. and R.P. contributed to genetic and bioinformatic analyses. K.H., K.C., R.Q., Y.-L.A.H., K.R., M.A. and D.P. contributed to phenotyping and phenomic analyses. The initial manuscript was drafted by M.B.S., D.F.L., R.P. and J.G. Manuscript contributions and interpretation of results were provided by M.B.S., D.F.L., Z.C., F.R.W., G.A.P., K.H., M.J.G., D.P., R.S.D., H.Z., R.P., J.C. and J.G. The remaining authors contributed to other organizational or data-processing components of the study. All authors saw, had the opportunity to comment on and approved the final draft.

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Correspondence to Murray B. Stein or Joel Gelernter.

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Competing interests

M.B.S. has in the past 3 years been a consultant for Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, Epivario, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, Roche/Genentech and Oxeia Biopharmaceuticals. M.B.S. has stock options in Oxeia Biopharmaceuticals and Epivario. J.G. is named as coinventor on PCT patent application no. 15/878,640, entitled ‘Genotype-guided dosing of opioid agonists’, filed 24 January 2018. None of the other authors declare any competing interests.

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Extended data

Extended Data Fig. 1 Manhattan plot of MVP AFR case-control GWAS.

Horizontal red line indicates P < 5 × 10−8. P-values are uncorrected. Results are based on logistic regression.

Extended Data Fig. 2 Polygenic risk scores in MVP and PGC-PTSD.

Polygenic risk score (PRS) from MVP EUR case-control (left) and EUR PCL-total (right) applied to PGC-PTSD13 case-control phenotype with varying P-value thresholds (PT) on the x-axis and explained variance (R2) on the y-axis. The approximate estimate of the explained variance was calculated using a multivariate regression model. P values reported are two sided, and Bonferroni correction accounting for the number of P-value thresholds tested is P = 2.38 × 10−4.

Extended Data Fig. 3 Symptom and polygenic risk scores in veterans of African and European ancestry.

Top shows density plot of PCL-total scores in veterans of AFR (salmon color) and EUR (teal color) ancestry. Bottom shows density plot of PRS scores (at P-value threshold 0.001) for MVP PCL AFR (salmon color) and MVP PCL EUR (teal color) derived from PGC PTSD EUR.

Extended Data Fig. 4 Gene Ontology (GO) term and GTEx tissue enrichment.

a, Quantile-quantile plots between Gene Ontology (GO) term enrichment (one-sided test for positive relationship between tissue and genetic association) in original PCL-Total and conditioned PCL-Total (blue, autism spectrum disorder; purple, major depression; dark green, anorexia nervosa; light green, anxiety; pink, schizophrenia; light blue, bipolar disorder; orange, attention deficit hyperactivity disorder; red, all eight disorders simultaneously). b, Quantile-quantile relationship between GTEx tissue enrichment (one-sided test for positive relationship between tissue and genetic association) in original PCL-total and conditioned PCL-Total. To avoid over-plotting, enrichment P-values were divided into quantiles. Red diagonal lines indicate a one-to-one relationship between original and conditioned PCL-Total gene set and tissue enrichments. Two-sided tests were used to compare enrichment results.

Supplementary information

Supplementary Information

Supplementary Note, Figs. 1 and 2 and Tables 1–7

Reporting Summary

Supplementary Data 1

Fine-mapping of risk loci

Supplementary Data 2

Regulatory variant prioritization and colocalization with eQTL for PCL-Total

Supplementary Tables 8–10

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Stein, M.B., Levey, D.F., Cheng, Z. et al. Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program. Nat Genet 53, 174–184 (2021). https://doi.org/10.1038/s41588-020-00767-x

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