Abstract
Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.
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Data availability
Summary statistics for PGC-PTSD Freeze 3 will be made available upon publication under the accession ID ptsd2024 via the PGC website (https://pgc.unc.edu/for-researchers/download-results/). Access to study-level summary statistics and genotype data can be applied by using the PGC data access portal (https://pgc.unc.edu/for-researchers/data-access-committee/data-access-portal/).
Code availability
Analysis code is made available at GitHub (https://github.com/nievergeltlab/freeze3_gwas) and Zenodo (https://doi.org/10.5281/zenodo.10182702)118.
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Acknowledgements
Major financial support for the PTSD-PGC was provided by the National Institute of Mental Health (NIMH; R01MH106595 (to K.C.K., C.M.N., K.J.R. and M.B.S.), R01MH124847 (to C.M.N.) and R01MH124851 (to A.D.B., L.K.D. and K.C.K.)), the Stanley Center for Psychiatric Research at the Broad Institute and Cohen Veterans Bioscience. Statistical analyses were carried out on the NL Genetic Cluster computer (URL) hosted by SURFsara. Genotyping of samples was supported in part through the Stanley Center for Psychiatric Genetics at the Broad Institute of MIT and Harvard. This research has been conducted using the UKB resource under application 41209. This work would not have been possible without the contributions of the investigators who comprise the PGC-PTSD working group, and especially the more than 1,307,247 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank A.E. Aiello, B. Bradley, A. Gautam, R. Hammamieh, M. Jett, M.J. Lyons, D. Maurer, M.R. Mavissakalian and the late C.R. Erbes and R.E. McGlinchey for their contributions to this study.
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E.G.A., S.-A.B., C.-Y.C., K.W.C., J.R.I.C., N.P.D., L.E.D., K.C.K., A.X.M., R.A.M., C.M.N., R.P., K.J.R. and M.B.S. were the members of the PGC-PTSD writing group. A.B.A., S.B. Andersen, P.A.A., A.E.A.-K., S.B. Austin, E.A., D.B., D.G.B., J.C.B., S. Belangero, C. Benjet, J.M.B., L.J.B., J.I.B., G.B., R.B., A.D.B., J.R.C., C.S.C., L.K.B., J.D., D.L.D., T.d.-C., K.D., G.D., A.D.-K., N.F., L.A.F., A.F., N.C.F., B.G., J.G., E.G., C.F.G., A.G.U., M.A.H., A.C.H., V.H., I.B.H., D.M.H., K. Hveem, M. Jakovljević, A.J., I.J., T.J., K.-I.K., M.L.K., R.C.K., N.A.K., K.C.K., R.K., H.R.K., W.S.K., B.R.L., K.L., I.L., B.L., C.M., N.G.M., K.A.M., S.A.M., S.E.M., D.M., W.P.M., M.W.M., C.P.M., O.M., P.B.M, E.C.N., C.M.N., M.N., S.B.N., N.R.N., P.M.P., A.L.P., R.H.P., M.A.P., B.P., A.P., K.J.R., V.R., P.R.B., K.R., H.R., G.S., S. Seedat, J.S. Seng, A.K.S., S.R.S., D.J.S., M.B.S., R.J.U., U.V., S.J.H.v.R., E.V., J.V., Z.W., M.W., H.W., T.W., M.A.W., D.E.W., C.W., R.M.Y., H.Z., L.A.Z. and J.-A.Z. were the principal investigators or co-principal investigators of contributing studies. A.B.A., P.A.A., A.E.A.-K., S.B. Austin, J.C.B., S. Belangero, C. Benjet, J.M.B., L.J.B., G.B., A.D.B., C.S.C., J.D., T.d.-C., A.F., N.C.F., J.D.F., C.E.F., E.G., C.F.G., M.H., M.A.H., A.C.H., V.H., I.B.H., D.M.H., K. Hveem, T.J., N.A.K., K.C.K., R.K., W.S.K., B.R.L., B.L., C.M., N.G.M., K.A.M., S.A.M., S.E.M., J.M., W.P.M., M.W.M., C.P.M., O.M., P.B.M, E.C.N., C.M.N., M.N., N.R.N., H.K.O., M.A.P., B.P., K.J.R., B.O.R., G.S., M.S., A.K.S., S.R.S., M.H.T., R.J.U., U.V., E.V., J.V., Z.W., M.W., T.W., M.A.W., D.E.W., R.Y., R.M.Y. and L.A.Z. obtained funding for studies. C.A., P.A.A., E.A., D.B., D.G.B., J.C.B., L.B., L.J.B., E.A.B., R.B., A.C.B., A.D.B., S. Børte, L.C., J.R.C., K.W.C., L.K.B., M.F.D., T.d.-C., S.G.D., G.D., A.D.-K., N.F., N.C.F., J.D.F., C.E.F., S.G., E.G., A.G.U., S.B.G., L.G., C.G., V.H., D.M.H., M. Jakovljević, A.J., G.D.J., M.L.K., A.K., N.A.K., N.K., R.K., W.S.K., B.R.L., L.A.M.L., K.L., C.E.L., B.L., J.L.M.-K., S.A.M., P.B.M., H.K.O., P.M.P., M.S.P., E.S.P., A.L.P., M.P., R.H.P., M.A.P., B.P., A.P., B.O.R., A.O.R., G.S., L.S., J.S. Seng, C.M.S., S. Stensland, M.H.T., W.K.T., E.T., M.U., U.V., L.L.v.d.H., E.V., Z.W., Y.W., T.W., D.E.W., B.S.W., S.W., E.J.W., R.Y., K.A.Y. and L.A.Z. were responsible for clinical aspects of studies. O.A.A., P.A.A., S.B. Austin, D.G.B., S. Belangero, L.J.B., R.B., R.A.B., A.D.B., J.R.C., J.M.C.-d.-A., S.Y.C., S.A.P.C., A.M.D., L.K.B., D.L.D., A.E., N.C.F., D.F., C.E.F., S.G., B.G., S.M.J.H., D.M.H., L.M.H., K. Hveem, A.J., I.J., M.L.K., J.L.K., R.C.K., A.P.K., R.K., W.S.K., L.A.M.L., K.L., D.F.L., C.E.L., I.L., B.L., M.K.L., S.M., G.A.M., K.M., A.M., K.A.M., S.E.M., J.M., L.M., O.M., P.B.M., M.N., S.B.N., N.R.N., M.O., P.M.P., M.S.P., E.S.P., A.L.P., M.P., R.H.P., M.A.P., K.J.R., V.R., P.R.B., A. Rung, G.S., L.S., S.E.S., M.S., C.S., S. Seedat, J.S. Seng, D. Silove, J.W.S., S.R.S., M.B.S., A.K.T., E.T., U.V., L.L.v.d.H., M.V.H., M.W., T.W., D.E.W., S.W., K.A.Y., C.C.Z., G.C.Z., L.A.Z. and J.-A.Z. contributed to data collection. A.E.A.-K., A. Batzler, C. Bergner, A. Brandolino, S. Børte, C.C., C.-Y.C., S.A.P.C., J.R.I.C., L.C.-C., B.J.C., S.D., S.G.D., A.D., L.E.D., C.F., M.E.G., B.G., S.B.G., S.D.G., C.G., S.H., E.M.H., K. Hogan, H.H., G.D.J., K.K., P.-F.K., D.F.L., M.W.L., A.L, Y.L., A.X.M., S.M., C.M., D.M., J.M., V.M., E.A.M., M.S.M., C.M.N., G.A.P., M.P., X.-J.Q., A.R., A.L.R., S.S.d.V., C.S., A.S., C.M.S., S. Stensland, J.S.S., J.A.S., F.R.W., B.S.W., Y. Xia, Y. Xiong and C.C.Z. conducted statistical analysis. A.E.A.-K., A. Batzler, M.P.B., S. Børte, C.C., C.-Y.C., J.R.I.C., N.P.D., C.D.P., S.G.D., A.D., H.E., M.E.G., K. Hogan, H.H., K.K., P.-F.K., D.F.L., S.D.L., A.L, A.X.M., G.A.M., D.M., J.M., V.M., E.A.M., G.A.P., A.R., A.S., J.S.S., F.R.W., B.S.W., C.W., Y. Xia, Y. Xiong and C.C.Z. conducted bioinformatics analysis. M.P.B., J.B.-G., M.B.-H., N.P.D., T.d.-C., F.D., A.D., K.D., H.E., L.G., M.A.H., J.J., P.-F.K., S.D.L., J.J.L., I.K., J.M., L.M., K.J.R., B.P.F.R., S.S.d.V., A.S., C.H.V. and D.E.W. conducted genomics studies. M.H. and M.Z were the members of the PGC-PTSD management group.
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L.J.B. is listed as an inventor on Issued US Patent 8,080,371, ‘Markers for Addiction’ covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction. C.-Y.C. and H.R. are employees of Biogen. A.M.D. holds equity in CorTechs Labs and serves on the Scientific Advisory Board of Human Longevity and the Mohn Medical Imaging and Visualization Center. A.M.D. receives funding through research grants with General Electric Healthcare. C.F. was a speaker for Janssen in 2021. I.B.H. is the codirector, Health and Policy at the Brain and Mind Center (BMC) University of Sydney; the BMC operates early intervention youth services at Camperdown under contract to headspace; and is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty; InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the AU$30 million Australian Government-funded Project Synergy. H.H. received consultancy fees from Ono Pharmaceutical and an honorarium from Xian Janssen Pharmaceutical. In the past 3 years, R.C.K. was a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, RallyPoint Networks and Sage Therapeutics. He has stock options in Cerebral, Mirah, PYM, Roga Sciences and Verisense Health. L.A.M.L. reports spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. C.M. has served on advisory boards of Receptor Life Sciences, Otsuka Pharmaceuticals and Roche Products Limited and has received support from the National Institute on Alcohol Abuse and Alcoholism, NIMH, Department of Defense-CDMRP (US Army Research Office) DARPA, Bank of America Foundation, Brockman Foundation, Cohen Veterans Bioscience, Cohen Veterans Network, McCormick Foundation, Home Depot Foundation, New York City Council, New York State Health, Mother Cabrini Foundation, Tilray Pharmaceuticals and Ananda Scientific. P.M.P. received payment or honoraria for lectures and presentations in educational events for Sandoz, Daiichi Sankyo, Eurofarma, Abbot, Libbs, Instituto Israelita de Pesquisa e Ensino Albert Einstein, Instituto D’Or de Pesquisa e Ensino. R.P. has been paid for his editorial work on the journal Complex Psychiatry and received a research grant outside the scope of this study from Alkermes. J.W.S. is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity) and has received grant support from Biogen; and is the principal investigator of a collaborative study of the genetics of depression and BPD sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. M.B.S. has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sage Therapeutics, Sumitomo Pharma and Roche/Genentech; has stock options in Oxeia Biopharmaceuticals and EpiVario; has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor) and UpToDate (Coeditor-in-Chief for Psychiatry); has also received research support from NIH, Department of Veterans Affairs and the Department of Defense; and is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. In the past 3 years, D.J.S. has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. M.L.K. reports unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Comparison of the genetic architecture of PTSD in the three main data sources.
Quantification of polygenicity and polygenic overlap in the three main data subsets based on (1) symptom scores in clinical studies and cohorts assessed on a variety of instruments in Freeze 2.5 (yellow; 26,080 cases and 192,966 controls), (2) PCL (for DSM-IV) based symptom scores in the MVP (red; 32,372 cases and 154,317 controls) and (3) ICD9/10 codes in EHR studies (blue; 78,684 cases and 738,463 controls) indicate a similar genetic architecture. The circles on the top half of the plot depict univariate MiXeR estimates of the total polygenicity for each data subset. Numbers within circles indicate polygenicity values, expressed as the number of variants (in thousands, with s.e. in parenthesis) necessary to explain 90% of SNP-based heritability (h2SNP). h2SNP estimates are written in the boxes at the bottom of the circles. The Euler diagrams on the bottom half of the plot depict bivariate MiXeR estimates of the polygenic overlap between data subsets. Values in the overlapping part of the Euler diagrams denote shared polygenicity and values on the non-overlapping parts note dataset-specific polygenicity. Genetic correlations (rg) between dataset pairs are noted in the boxes below the Euler diagrams. Arrowed lines are drawn between univariate and bivariate results to indicate which dataset pairs are being evaluated.
Extended Data Fig. 2 Manhattan plot of the PTSD GWAS meta-analysis in individuals of European ancestry (EA).
Results of the EA GWAS meta-analysis (137,136 PTSD cases, 1,085,746 controls) identifying 81 genome-wide significant PTSD loci. The y-axis refers to the −log10 P value from two-sided z-tests for effect estimates for a meta-analysis using a sample size weighted fixed-effects model. Circle colors alternate between chromosomes: even chromosomes are colored blue and odd chromosomes are colored black. The horizontal red bar indicates genome-wide significant associations (P < 5 × 10−8).
Extended Data Fig. 3 Significant PTSD gene sets.
MAGMA gene-set analysis using the Molecular Signatures Database (MSigDB) identifies 12 significant gene sets. The dotted line indicates significance adjusted for the number of comparisons (P < 0.05/15,483 gene sets). Bars depict −log10 P values from one-sided t-tests for enrichment. Corresponding gene-set names are indicated to the left of bars. Terms are clustered and colored according to their Gene Ontology term category (biological processes, yellow; molecular function, blue; cellular component, red).
Extended Data Fig. 4 MAGMA tissue enrichment analysis.
MAGMA gene-property analysis in 53 specific tissue types from GTEx v8 shows enrichment of PTSD-related genes in 13 brain tissue types and in the pituitary. Bars depict −log10 P values from one-sided t-tests for enrichment. Corresponding tissue names are indicated below bars. The dotted horizontal line indicates statistical significance adjusted for the number of comparisons (P < 0.05/53). Significant tissues are colored red.
Extended Data Fig. 5 MAGMA cell-type enrichment analysis in midbrain.
MAGMA gene-property analysis of 25 midbrain cell types (GSE76381) indicates enrichment of GABAergic neurons, GABAergic neuroblasts and mediolateral neuroblasts. Vertical bars depict −log10 P values from one-sided t-tests for enrichment. Significant cell types are colored blue and gray if not. The dotted horizontal line indicates statistical significance adjusted for the number of comparisons (P < 0.05/25). The asterisk (*) indicates that GABAergic neurons remained significant in stepwise conditional analysis of the other significant cell types. Abbreviations: Gaba, GABAergic neurons; NbGaba, neuroblast gabaergic; NbML1-5, mediolateral neuroblasts; DA0-2, dopaminergic neurons; Sert, serotonergic neurons; RN, red nucleus; Rgl 1-3, radial glia-like cells; NbM, medial neuroblasts; OPC, oligodendrocyte precursor cells; ProgFPL, progenitor lateral floorplate; OMTN, oculomotor and trochlear nucleus; Endo, endothelial cells; ProgM, progenitor midline; NProg, neuronal progenitor; ProgBP, progenitor basal plate; Mgl, microglia; ProgFPM, progenitor medial floorplate; Peric, pericytes.
Extended Data Fig. 6 PTSD genes in SynGO.
Sunburst plots show enrichment of PTSD-related genes in SynGO cellular components. The synapse is at the center ring, pre- and post-synaptic locations are at the first rings, and child terms are in subsequent outer rings. a, Enrichment test results for all 415 genes mapped to PTSD GWAS loci by FUMA from one of three gene-mapping strategies (positional, expression quantitative trait loci and chromatin interaction mapping). b, Enrichment test results for 43 genes prioritized into tier 1 using a gene prioritization strategy. Plots are colored by −log10 Q-value (see color code in the bar at left) from enrichment of PTSD genes relative to a brain-expressed background set.
Extended Data Fig. 7 Genetic correlations and polygenic overlap between PTSD and other psychiatric disorders.
a, Genetic correlations (rg) with standard error between PTSD and 11 other psychiatric disorders are indicated by circles that are drawn along the x-axis. Red dots indicate SNP-based heritability (h2SNP) z-score >6 in the psychiatric disorder GWAS and colored gray to indicate z-score <6 (rg estimates may be unreliable). The first author and publication year of source summary data are noted in parenthesis following the disorder name. b, Quantification of the polygenic overlap between PTSD and other psychiatric disorders. Euler diagrams depict Bivariate MiXeR analysis of PTSD (blue circles) and bipolar disorder (BIP), major depression (MDD) and schizophrenia (SCZ) (red circles). Values in the overlapping part of the Euler diagrams denote shared polygenicity (expressed as the number of influential variants, in thousands, with s.e. in parenthesis), and values in the non-overlapping part indicate dataset-specific variation. rg between dataset pairs are noted in the boxes below the Euler plots. Abbreviations: ADHD, attention deficit hyperactive disorder; Alc. dep., alcohol dependence; BIP, bipolar disorder; MDD, major depression; OCD, obsessive compulsive disorder; SCZ, schizophrenia.
Supplementary information
Supplementary Information
Supplementary Note and Figs. 1–10.
Supplementary Tables
Supplementary Tables 1–31.
Supplementary Data 1
Regional association plots for each significant locus from the EA GWAS meta-analysis.
Supplementary Data 2
Forest plots for each of the 81 index variants of the GWAS loci identified in the EA GWAS meta-analysis.
Supplementary Data 3
Circos plots of chromatin interactions and eQTLs for each chromosome with PTSD risk loci based on the EA GWAS meta-analysis.
Supplementary Data 4
Gene prioritization scores and rankings for all 415 protein-coding genes mapped to risk loci.
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Nievergelt, C.M., Maihofer, A.X., Atkinson, E.G. et al. Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder. Nat Genet (2024). https://doi.org/10.1038/s41588-024-01707-9
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DOI: https://doi.org/10.1038/s41588-024-01707-9
