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

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

doi:10.1038/s41467-019-12576-w

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

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

Department of Clinical Medicine

54 Citations (Scopus)

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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.

Original language	English
Article number	4558
Journal	Nature Communications
Volume	10
Issue number	1
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-019-12576-w
Publication status	Published - 1 Dec 2019

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s41467-019-12576-wFinal published version, 3.13 MBLicence: CC BY

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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., ... Koenen, K. C. (2019). International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nature Communications, 10(1), Article 4558. https://doi.org/10.1038/s41467-019-12576-w

Nievergelt, CM, Maihofer, AX, Klengel, T, Atkinson, EG, Chen, C-Y, Choi, KW, Coleman, JRI, Dalvie, S, Duncan, LE, Gelernter, J, Levey, DF, Logue, MW, Polimanti, R, Provost, AC, Ratanatharathorn, A, Stein, MB, Torres, K, Aiello, AE, Almli, LM, Amstadter, AB, Andersen, SB, Andreassen, OA, Arbisi, PA, Ashley-Koch, AE, Austin, SB, Avdibegovic, E, Babić, D, Bækvad-Hansen, M, Baker, DG, Beckham, JC, Bierut, LJ, Bisson, JI, Boks, MP, Bolger, EA, Børglum, AD, Bradley, B, Brashear, M, Breen, G, Bryant, RA, Bustamante, AC, Bybjerg-Grauholm, J, Calabrese, JR, Caldas- de- Almeida, JM, Dale, AM, Daly, MJ, Daskalakis, NP, Deckert, J, Delahanty, DL, Dennis, MF, Disner, SG, Domschke, K, Dzubur-Kulenovic, A, Erbes, CR, Evans, A, Farrer, LA, Feeny, NC, Flory, JD, Forbes, D, Franz, CE, Galea, S, Garrett, ME, Gelaye, B, Geuze, E, Gillespie, C, Uka, AG, Gordon, SD, Guffanti, G, Hammamieh, R, Harnal, S, Hauser, MA, Heath, AC, Hemmings, SMJ, Hougaard, DM, Jakovljevic, M, Jett, M, Johnson, EO, Jones, I, Jovanovic, T, Qin, X-J, Junglen, AG, Karstoft, K-I, Kaufman, ML, Kessler, RC, Khan, A, Kimbrel, NA, King, AP, Koen, N, Kranzler, HR, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, CE, Linnstaedt, SD, Lori, A, Lugonja, B, Luykx, JJ, Lyons, MJ, Maples-Keller, J, Marmar, C, Martin, AR, Martin, NG, Maurer, D, Mavissakalian, MR, McFarlane, A, McGlinchey, RE, McLaughlin, KA, McLean, SA, McLeay, S, Mehta, D, Milberg, WP, Miller, MW, Morey, RA, Morris, CP, Mors, O, Mortensen, PB, Neale, BM, Nelson, EC, Nordentoft, M, Norman, SB, O’Donnell, M, Orcutt, HK, Panizzon, MS, Peters, ES, Peterson, AL, Peverill, M, Pietrzak, RH, Polusny, MA, Rice, JP, Ripke, S, Risbrough, VB, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, K, Rung, A, Rutten, BPF, Saccone, NL, Sanchez, SE, Schijven, D, Seedat, S, Seligowski, AV, Seng, JS, Sheerin, CM, Silove, D, Smith, AK, Smoller, JW, Sponheim, SR, Stein, DJ, Stevens, JS, Sumner, JA, Teicher, MH, Thompson, WK, Trapido, E, Uddin, M, Ursano, RJ, van den Heuvel, LL, Van Hooff, M, Vermetten, E, Vinkers, CH, Voisey, J, Wang, Y, Wang, Z, Werge, T, Williams, MA, Williamson, DE, Winternitz, S, Wolf, C, Wolf, EJ, Wolff, JD, Yehuda, R, Young, RM, Young, KA, Zhao, H, Zoellner, LA, Liberzon, I, Ressler, KJ, Haas, M & Koenen, KC 2019, 'International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci', Nature Communications, vol. 10, no. 1, 4558. https://doi.org/10.1038/s41467-019-12576-w

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

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{\textquoteright}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.",

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

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-12576-w",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

number = "1",

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TY - JOUR

T1 - International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

AU - Nievergelt, Caroline M.

AU - Maihofer, Adam X.

AU - Klengel, Torsten

AU - Atkinson, Elizabeth G.

AU - Chen, Chia-Yen

AU - Choi, Karmel W.

AU - Coleman, Jonathan R. I.

AU - Dalvie, Shareefa

AU - Duncan, Laramie E.

AU - Gelernter, Joel

AU - Levey, Daniel F.

AU - Logue, Mark W.

AU - Polimanti, Renato

AU - Provost, Allison C.

AU - Ratanatharathorn, Andrew

AU - Stein, Murray B.

AU - Torres, Katy

AU - Aiello, Allison E.

AU - Almli, Lynn M.

AU - Amstadter, Ananda B.

AU - Andersen, Søren B.

AU - Andreassen, Ole A.

AU - Arbisi, Paul A.

AU - Ashley-Koch, Allison E.

AU - Austin, S. Bryn

AU - Avdibegovic, Esmina

AU - Babić, Dragan

AU - Bækvad-Hansen, Marie

AU - Baker, Dewleen G.

AU - Beckham, Jean C.

AU - Bierut, Laura J.

AU - Bisson, Jonathan I.

AU - Boks, Marco P.

AU - Bolger, Elizabeth A.

AU - Børglum, Anders D.

AU - Bradley, Bekh

AU - Brashear, Megan

AU - Breen, Gerome

AU - Bryant, Richard A.

AU - Bustamante, Angela C.

AU - Bybjerg-Grauholm, Jonas

AU - Calabrese, Joseph R.

AU - Caldas- de- Almeida, José M.

AU - Dale, Anders M.

AU - Daly, Mark J.

AU - Daskalakis, Nikolaos P.

AU - Deckert, Jürgen

AU - Delahanty, Douglas L.

AU - Dennis, Michelle F.

AU - Disner, Seth G.

AU - Domschke, Katharina

AU - Dzubur-Kulenovic, Alma

AU - Erbes, Christopher R.

AU - Evans, Alexandra

AU - Farrer, Lindsay A.

AU - Feeny, Norah C.

AU - Flory, Janine D.

AU - Forbes, David

AU - Franz, Carol E.

AU - Galea, Sandro

AU - Garrett, Melanie E.

AU - Gelaye, Bizu

AU - Geuze, Elbert

AU - Gillespie, Charles

AU - Uka, Aferdita Goci

AU - Gordon, Scott D.

AU - Guffanti, Guia

AU - Hammamieh, Rasha

AU - Harnal, Supriya

AU - Hauser, Michael A.

AU - Heath, Andrew C.

AU - Hemmings, Sian M. J.

AU - Hougaard, David Michael

AU - Jakovljevic, Miro

AU - Jett, Marti

AU - Johnson, Eric Otto

AU - Jones, Ian

AU - Jovanovic, Tanja

AU - Qin, Xue-Jun

AU - Junglen, Angela G.

AU - Karstoft, Karen-Inge

AU - Kaufman, Milissa L.

AU - Kessler, Ronald C.

AU - Khan, Alaptagin

AU - Kimbrel, Nathan A.

AU - King, Anthony P.

AU - Koen, Nastassja

AU - Kranzler, Henry R.

AU - Kremen, William S.

AU - Lawford, Bruce R.

AU - Lebois, Lauren A. M.

AU - Lewis, Catrin E.

AU - Linnstaedt, Sarah D.

AU - Lori, Adriana

AU - Lugonja, Bozo

AU - Luykx, Jurjen J.

AU - Lyons, Michael J.

AU - Maples-Keller, Jessica

AU - Marmar, Charles

AU - Martin, Alicia R.

AU - Martin, Nicholas G.

AU - Maurer, Douglas

AU - Mavissakalian, Matig R.

AU - McFarlane, Alexander

AU - McGlinchey, Regina E.

AU - McLaughlin, Katie A.

AU - McLean, Samuel A.

AU - McLeay, Sarah

AU - Mehta, Divya

AU - Milberg, William P.

AU - Miller, Mark W.

AU - Morey, Rajendra A.

AU - Morris, Charles Phillip

AU - Mors, Ole

AU - Mortensen, Preben B.

AU - Neale, Benjamin M.

AU - Nelson, Elliot C.

AU - Nordentoft, Merete

AU - Norman, Sonya B.

AU - O’Donnell, Meaghan

AU - Orcutt, Holly K.

AU - Panizzon, Matthew S.

AU - Peters, Edward S.

AU - Peterson, Alan L.

AU - Peverill, Matthew

AU - Pietrzak, Robert H.

AU - Polusny, Melissa A.

AU - Rice, John P.

AU - Ripke, Stephan

AU - Risbrough, Victoria B.

AU - Roberts, Andrea L.

AU - Rothbaum, Alex O.

AU - Rothbaum, Barbara O.

AU - Roy-Byrne, Peter

AU - Ruggiero, Ken

AU - Rung, Ariane

AU - Rutten, Bart P. F.

AU - Saccone, Nancy L.

AU - Sanchez, Sixto E.

AU - Schijven, Dick

AU - Seedat, Soraya

AU - Seligowski, Antonia V.

AU - Seng, Julia S.

AU - Sheerin, Christina M.

AU - Silove, Derrick

AU - Smith, Alicia K.

AU - Smoller, Jordan W.

AU - Sponheim, Scott R.

AU - Stein, Dan J.

AU - Stevens, Jennifer S.

AU - Sumner, Jennifer A.

AU - Teicher, Martin H.

AU - Thompson, Wesley K.

AU - Trapido, Edward

AU - Uddin, Monica

AU - Ursano, Robert J.

AU - van den Heuvel, Leigh Luella

AU - Van Hooff, Miranda

AU - Vermetten, Eric

AU - Vinkers, Christiaan H.

AU - Voisey, Joanne

AU - Wang, Yunpeng

AU - Wang, Zhewu

AU - Werge, Thomas

AU - Williams, Michelle A.

AU - Williamson, Douglas E.

AU - Winternitz, Sherry

AU - Wolf, Christiane

AU - Wolf, Erika J.

AU - Wolff, Jonathan D.

AU - Yehuda, Rachel

AU - Young, Ross McD.

AU - Young, Keith A.

AU - Zhao, Hongyu

AU - Zoellner, Lori A.

AU - Liberzon, Israel

AU - Ressler, Kerry J.

AU - Haas, Magali

AU - Koenen, Karestan C.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-019-12576-w

DO - 10.1038/s41467-019-12576-w

M3 - Journal article

C2 - 31594949

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4558

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

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