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Cited by 643Posttraumatic Stress Disorder ResearchGenetic Associations and EpidemiologyNeurotransmitter Receptor Influence on Behavior

The DOI matches its Crossref record; 95 of the 95 references it cites were found in a registry or an index.

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

Open access
Nievergelt, Caroline M., Maihofer, Adam X., Klengel, Torsten, Atkinson, Elizabeth G., Chen, Chia-Yen, Choi, Karmel W., Coleman, Jonathan R. I., Dalvie, Shareefa, Duncan, Laramie E., Gelernter, Joel, Levey, Daniel F., Logue, Mark W., Polimanti, Renato, Provost, Allison C., Ratanatharathorn, Andrew, Stein, Murray B., Torres, Katy, Aiello, Allison E., Almli, Lynn M., Amstadter, Ananda B., Andersen, Søren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegovic, Esmina, Babić, Dragan, Bækvad-Hansen, Marie, Baker, Dewleen G., Beckham, Jean C., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Børglum, Anders D., Bradley, Bekh, Brashear, Megan, Breen, Gerome, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Calabrese, Joseph R., Caldas- de- Almeida, José M., Dale, Anders M., Daly, Mark J., Daskalakis, Nikolaos P., Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Disner, Seth G., Domschke, Katharina, Dzubur-Kulenovic, Alma, Erbes, Christopher R., Evans, Alexandra, Farrer, Lindsay A., Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gelaye, Bizu, Geuze, Elbert, Gillespie, Charles, Uka, Aferdita Goci, Gordon, Scott D., Guffanti, Guia, Hammamieh, Rasha, Harnal, Supriya, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M. J., Hougaard, David Michael, Jakovljevic, Miro, Jett, Marti, Johnson, Eric Otto, Jones, Ian, Jovanovic, Tanja, Qin, Xue-Jun, Junglen, Angela G., Karstoft, Karen-Inge, Kaufman, Milissa L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kranzler, Henry R., Kremen, William S., Lawford, Bruce R., Lebois, Lauren A. M., Lewis, Catrin E., Linnstaedt, Sarah D., Lori, Adriana, Lugonja, Bozo, Luykx, Jurjen J., Lyons, Michael J., Maples-Keller, Jessica, Marmar, Charles, Martin, Alicia R., Martin, Nicholas G., Maurer, Douglas, Mavissakalian, Matig R., McFarlane, Alexander, McGlinchey, Regina E., McLaughlin, Katie A., McLean, Samuel A., McLeay, Sarah, Mehta, Divya, Milberg, William P., Miller, Mark W., Morey, Rajendra A., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben B., Neale, Benjamin M., Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., O’Donnell, Meaghan, Orcutt, Holly K., Panizzon, Matthew S., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Rice, John P., Ripke, Stephan, Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Ken, Rung, Ariane, Rutten, Bart P. F., Saccone, Nancy L., Sanchez, Sixto E., Schijven, Dick, Seedat, Soraya, Seligowski, Antonia V., Seng, Julia S., Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Sponheim, Scott R., Stein, Dan J., Stevens, Jennifer S., Sumner, Jennifer A., Teicher, Martin H., Thompson, Wesley K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., van den Heuvel, Leigh Luella, Van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan H., Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Wolff, Jonathan D., Yehuda, Rachel, Young, Ross McD., Young, Keith A., Zhao, Hongyu, Zoellner, Lori A., Liberzon, Israel, Ressler, Kerry J., Haas, Magali, Koenen, Karestan C.·2019·Nature Communications
DOI 10.1038/s41467-019-12576-wPMC PMC6783435
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Abstract

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2 , is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

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Fig. 1 Manhattan plots from meta-analyses of PTSD GWAS, showing the top variants in six independent genome-wide significant loci. Results are shown for subjects of European (EUA; a) and African ancestry (AFA; c), and for sex-stratified analyses in EUA men (b) and AFA men (d), respectively. Sex-stratified analyses for women were not significant (Supplementary Fig. 4). The red line represents genome-wide significance at P < 5 × 10−8. Note: rs148757321 and rs142174523 do not remain significant after Bonferroni-adjustment for sex-stratified analyses (at P < 1.67 × 10−8)
Fig. 1 Manhattan plots from meta-analyses of PTSD GWAS, showing the top variants in six independent genome-wide significant loci. Results are shown for subjects of European (EUA; a) and African ancestry (AFA; c), and for sex-stratified analyses in EUA men (b) and AFA men (d), respectively. Sex-stratified analyses for women were not significant (Supplementary Fig. 4). The red line represents genome-wide significance at P < 5 × 10−8. Note: rs148757321 and rs142174523 do not remain significant after Bonferroni-adjustment for sex-stratified analyses (at P < 1.67 × 10−8)CC BY · PubMed Central
Fig. 2 Genetic risk score (PRS) predictions for PTSD. a Using PTSD subjects from the UK Biobank (UKB) as discovery sample, odds ratios (OR) for PTSD per PRS quintile relative to the first quintile show a significant increase in different PGC PTSD target samples. For example, UKB men in the 5th quintile have 40% higher odds to develop PTSD than UKB men in the lowest quintile, when using women from the same population as a training set. b PRS predictions of re-experiencing symptoms in the external replication cohort from the Million Veteran Program (MVP) using the overall PGC2 as discovery sample show a highly significant increase in PTSD re-experiencing symptoms per PRS quintile. Sample sizes in different training and target sets include: UKB women: 6845 PTSD, 64,099 controls; UKB men: 3,544 PTSD, 51,700 controls; UKB: 10,389 PTSD, 115,799 controls; PGC1.5: 10,213 PTSD, 27,445 controls; PGC2: 23,212 PTSD, 151,447 controls; MVP: 146,660 participants with re-experiencing symptoms assessments. Analyses include only subjects of European ancestry
Fig. 2 Genetic risk score (PRS) predictions for PTSD. a Using PTSD subjects from the UK Biobank (UKB) as discovery sample, odds ratios (OR) for PTSD per PRS quintile relative to the first quintile show a significant increase in different PGC PTSD target samples. For example, UKB men in the 5th quintile have 40% higher odds to develop PTSD than UKB men in the lowest quintile, when using women from the same population as a training set. b PRS predictions of re-experiencing symptoms in the external replication cohort from the Million Veteran Program (MVP) using the overall PGC2 as discovery sample show a highly significant increase in PTSD re-experiencing symptoms per PRS quintile. Sample sizes in different training and target sets include: UKB women: 6845 PTSD, 64,099 controls; UKB men: 3,544 PTSD, 51,700 controls; UKB: 10,389 PTSD, 115,799 controls; PGC1.5: 10,213 PTSD, 27,445 controls; PGC2: 23,212 PTSD, 151,447 controls; MVP: 146,660 participants with re-experiencing symptoms assessments. Analyses include only subjects of European ancestryCC BY · PubMed Central
Fig. 3 Commonality of genetic correlations between PTSD and other psychiatric disorders and traits with GWAS summary statistics on LD Hub. Psychiatric traits include a PTSD, b MDD, c SCZ, d BPD and e ADHD and their genetic correlations with traits from psychiatric, anthropomorphic, smoking behavior, reproductive, aging, education, autoimmune and cardiometabolic categories. Only traits with at least one significant correlation with the 5 psychiatric disorders are shown. Error bars indicate 95% confidence limits. Solid points indicate significant correlation after Bonferroni correction. The total number of correlations tested were 235 for PTSD, 221 for MDD, 172 for SCZ, 196 for BPD and 219 for ADHD
Fig. 3 Commonality of genetic correlations between PTSD and other psychiatric disorders and traits with GWAS summary statistics on LD Hub. Psychiatric traits include a PTSD, b MDD, c SCZ, d BPD and e ADHD and their genetic correlations with traits from psychiatric, anthropomorphic, smoking behavior, reproductive, aging, education, autoimmune and cardiometabolic categories. Only traits with at least one significant correlation with the 5 psychiatric disorders are shown. Error bars indicate 95% confidence limits. Solid points indicate significant correlation after Bonferroni correction. The total number of correlations tested were 235 for PTSD, 221 for MDD, 172 for SCZ, 196 for BPD and 219 for ADHDCC BY · PubMed Central

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Research works printed but not linked: 2

  1. Anttila, V. et al. Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757 (2018). · DOI · Paper page
  2. Genomes Project, C. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015). · DOI · Paper page

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Authors
Nievergelt, C. M., Maihofer, A. X., Klengel, T., Atkinson, E. G., Chen, C.-Y., Choi, K. W., Coleman, J. R. I., Dalvie, S., Duncan, L. E., Gelernter, J., Levey, D. F., Logue, M. W., Polimanti, R., Provost, A. C., Ratanatharathorn, A., Stein, M. B., Torres, K., Aiello, A. E., Almli, L. M., Amstadter, A. B., Andersen, S. B., Andreassen, O. A., Arbisi, P. A., Ashley-Koch, A. E., Austin, S. B., Avdibegovic, E., Babić, D., Bækvad-Hansen, M., Baker, D. G., Beckham, J. C., Bierut, L. J., Bisson, J. I., Boks, M. P., Bolger, E. A., Børglum, A. D., Bradley, B., Brashear, M., Breen, G., Bryant, R. A., Bustamante, A. C., Bybjerg-Grauholm, J., Calabrese, J. R., Caldas- de- Almeida, J. M., Dale, A. M., Daly, M. J., Daskalakis, N. P., Deckert, J., Delahanty, D. L., Dennis, M. F., Disner, S. G., Domschke, K., Dzubur-Kulenovic, A., Erbes, C. R., Evans, A., Farrer, L. A., Feeny, N. C., Flory, J. D., Forbes, D., Franz, C. E., Galea, S., Garrett, M. E., Gelaye, B., Geuze, E., Gillespie, C., Uka, A. G., Gordon, S. D., Guffanti, G., Hammamieh, R., Harnal, S., Hauser, M. A., Heath, A. C., Hemmings, S. M. J., Hougaard, D. M., Jakovljevic, M., Jett, M., Johnson, E. O., Jones, I., Jovanovic, T., Qin, X.-J., Junglen, A. G., Karstoft, K.-I., Kaufman, M. L., Kessler, R. C., Khan, A., Kimbrel, N. A., King, A. P., Koen, N., Kranzler, H. R., Kremen, W. S., Lawford, B. R., Lebois, L. A. M., Lewis, C. E., Linnstaedt, S. D., Lori, A., Lugonja, B., Luykx, J. J., Lyons, M. J., Maples-Keller, J., Marmar, C., Martin, A. R., Martin, N. G., Maurer, D., Mavissakalian, M. R., McFarlane, A., McGlinchey, R. E., McLaughlin, K. A., McLean, S. A., McLeay, S., Mehta, D., Milberg, W. P., Miller, M. W., Morey, R. A., Morris, C. P., Mors, O., Mortensen, P. B., Neale, B. M., Nelson, E. C., Nordentoft, M., Norman, S. B., O’Donnell, M., Orcutt, H. K., Panizzon, M. S., Peters, E. S., Peterson, A. L., Peverill, M., Pietrzak, R. H., Polusny, M. A., Rice, J. P., Ripke, S., Risbrough, V. B., Roberts, A. L., Rothbaum, A. O., Rothbaum, B. O., Roy-Byrne, P., Ruggiero, K., Rung, A., Rutten, B. P. F., Saccone, N. L., Sanchez, S. E., Schijven, D., Seedat, S., Seligowski, A. V., Seng, J. S., Sheerin, C. M., Silove, D., Smith, A. K., Smoller, J. W., Sponheim, S. R., Stein, D. J., Stevens, J. S., Sumner, J. A., Teicher, M. H., Thompson, W. K., Trapido, E., Uddin, M., Ursano, R. J., van den Heuvel, L. L., Van Hooff, M., Vermetten, E., Vinkers, C. H., Voisey, J., Wang, Y., Wang, Z., Werge, T., Williams, M. A., Williamson, D. E., Winternitz, S., Wolf, C., Wolf, E. J., Wolff, J. D., Yehuda, R., Young, R. M., Young, K. A., Zhao, H., Zoellner, L. A., Liberzon, I., Ressler, K. J., Haas, M., & Koenen, K. C.
Affiliations
  • University of California San Diego (US)
  • Harvard University (US)
  • Broad Institute (US)
  • King's College London (GB)
  • University of Cape Town (ZA)
  • Stanford University (US)
  • United States Department of Veterans Affairs (US)
  • Yale University (US)
  • VA Boston Healthcare System (US)
  • Cohen Veterans Bioscience (US)
  • University of North Carolina at Chapel Hill (US)
  • Emory University (US)
  • The Danish Veteran Centre (DK)
  • University of Oslo (NO)
  • Minneapolis VA Health Care System (US)
  • Brigham and Women's Hospital (US)
  • Duke University (US)
  • Washington University in St. Louis (US)
  • Cardiff University (GB)
  • University Medical Center Utrecht (NL)
  • Aarhus University (DK)
  • Louisiana State University (US)
  • UNSW Sydney (AU)
  • University of Michigan (US)
  • University Hospitals of Cleveland (US)
  • Massachusetts General Hospital (US)
  • Universitätsklinikum Würzburg (DE)
  • Kent State University (US)
  • University of Freiburg (DE)
  • University of Minnesota (US)
  • Boston University (US)
  • Case Western Reserve University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • The University of Melbourne (AU)
  • University Clinical Center of Kosovo (XK)
  • QIMR Berghofer Medical Research Institute (AU)
  • United States Army Medical Research and Development Command (US)
  • Stellenbosch University (ZA)
  • Statens Serum Institut (DK)
  • RTI International (US)
  • University of Copenhagen (DK)
  • Philadelphia VA Medical Center (US)
  • Queensland University of Technology (AU)
  • New York University (US)
  • United States Army (US)
  • The University of Adelaide (AU)
  • Gallipoli Medical Research Foundation (AU)
  • Aarhus University Hospital (DK)
  • Northern Illinois University (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • University of Washington (US)
  • Medical University of South Carolina (US)
  • Maastricht University Medical Centre (NL)
  • Columbia University Irving Medical Center (US)
  • Oslo University Hospital (NO)
  • University of South Florida (US)
  • Uniformed Services University of the Health Sciences (US)
  • Leiden University Medical Center (NL)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • McLean Hospital (US)
  • James J. Peters VA Medical Center (US)
  • Central Texas Veterans Health Care System (US)
Corresponding author
Nievergelt, Caroline M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-10-08
Volume
10
Issue
1
Pages
4558-4558
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-12576-w
PMC
PMC6783435
OpenAlex
W2979994192
Cited by
635
References
88
Citations by year
2026: 58 · 2025: 107 · 2024: 128 · 2023: 105 · 2022: 111 · 2021: 82 · 2020: 35 · 2019: 7
FWCI
9.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • SUNScholar (Stellenbosch University) (submittedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Broad Institute
  • Cohen Veterans Bioscience
  • One Mind
  • Lundbeckfonden (R248‐2017‐2003)
  • Stanley Center for Psychiatric Research, Broad Institute
  • Medical Research Council (MR/L010305/1)
  • National Institute of Mental Health (U01MH109539, R21MH112956, T32MH017119, U01MH109536, K01MH118467, F32MH109274, R01MH103291, R01MH106595)
  • National Institute on Minority Health and Health Disparities (R01MD011728)
  • Medical Research and Materiel Command (R01MH106595)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
post-traumatic stress disorder, genetic susceptibility loci, sex differences, heritability, polygenic risk, re-experiencing symptoms, PARK2, dopaminergic modulation, non-coding RNA, Million Veteran Program, multi-ethnic cohort
MeSH terms
Female, Humans, Male, Sex Factors, Stress Disorders, Post-Traumatic, Veterans, Genetic Predisposition to Disease, Black People, White People, Ubiquitin-Protein Ligases, Genome-Wide Association Study, Genetic Loci, Datasets as Topic

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