Abstract
BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).
METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms.
RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program.
CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
Original language | English |
---|---|
Pages (from-to) | 626-636 |
Number of pages | 11 |
Journal | Biological Psychiatry |
Volume | 91 |
Issue number | 7 |
Early online date | 28 Sept 2021 |
DOIs | |
Publication status | Published - 1 Apr 2022 |
Keywords
- GENOME-WIDE ASSOCIATION
- LD SCORE REGRESSION
- METAANALYSIS
- PROLIFERATION
- PSYCHIATRIC GENOMICS
- PTSD
- RISK-FACTORS
- THOUSANDS
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In: Biological Psychiatry, Vol. 91, No. 7, 01.04.2022, p. 626-636.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information
AU - Maihofer, Adam X
AU - Choi, Karmel W
AU - Coleman, Jonathan R I
AU - Daskalakis, Nikolaos P
AU - Denckla, Christy A
AU - Ketema, Elizabeth
AU - Morey, Rajendra A
AU - Polimanti, Renato
AU - Ratanatharathorn, Andrew
AU - Torres, Katy
AU - Wingo, Aliza P
AU - Zai, Clement C
AU - Aiello, Allison E
AU - Almli, Lynn M
AU - Amstadter, Ananda B
AU - Andersen, Soren B
AU - Andreassen, Ole A
AU - Arbisi, Paul A
AU - Ashley-Koch, Allison E
AU - Austin, S Bryn
AU - Avdibegović, Esmina
AU - Borglum, Anders D
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 - Bradley, Bekh
AU - Brashear, Meghan
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 - Chen, Chia-Yen
AU - Dale, Anders M
AU - Dalvie, Shareefa
AU - Deckert, Jürgen
AU - Delahanty, Douglas L
AU - Dennis, Michelle F
AU - Disner, Seth G
AU - Domschke, Katharina
AU - Duncan, Laramie E
AU - Džubur Kulenović, 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 - Gautam, Aarti
AU - Gelaye, Bizu
AU - Gelernter, Joel
AU - Geuze, Elbert
AU - Gillespie, Charles F
AU - Goçi, Aferdita
AU - Gordon, Scott D
AU - Guffanti, Guia
AU - Hammamieh, Rasha
AU - Hauser, Michael A
AU - Heath, Andrew C
AU - Hemmings, Sian M J
AU - Hougaard, David Michael
AU - Jakovljević, Miro
AU - Jett, Marti
AU - Johnson, Eric Otto
AU - Jones, Ian
AU - Jovanovic, Tanja
AU - Qin, Xue-Jun
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
AU - Liberzon, Israel
AU - Linnstaedt, Sarah D
AU - Logue, Mark W
AU - Lori, Adriana
AU - Lugonja, Božo
AU - Luykx, Jurjen J
AU - Lyons, Michael J
AU - Maples-Keller, Jessica L
AU - Marmar, Charles
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 - Mehta, Divya
AU - Mellor, Rebecca
AU - Michopoulos, Vasiliki
AU - Milberg, William
AU - Miller, Mark W
AU - Morris, Charles Phillip
AU - Mors, Ole
AU - Mortensen, Preben B
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 - Risbrough, Victoria B
AU - Roberts, Andrea L
AU - Rothbaum, Alex O
AU - Rothbaum, Barbara O
AU - Roy-Byrne, Peter
AU - Ruggiero, Kenneth J
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 - 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
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 - Yehuda, Rachel
AU - Young, Keith A
AU - Young, Ross McD
AU - Zhao, Hongyu
AU - Zoellner, Lori A
AU - Haas, Magali
AU - Lasseter, Heather
AU - Provost, Allison C
AU - Salem, Rany M
AU - Sebat, Jonathan
AU - Shaffer, Richard A
AU - Wu, Tianying
AU - Ripke, Stephan
AU - Daly, Mark J
AU - Ressler, Kerry J
AU - Koenen, Karestan C
AU - Stein, Murray B
AU - Nievergelt, Caroline M
N1 - Copyright © 2021 Society of Biological Psychiatry. All rights reserved.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms.RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program.CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms.RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program.CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.
KW - GENOME-WIDE ASSOCIATION
KW - LD SCORE REGRESSION
KW - METAANALYSIS
KW - PROLIFERATION
KW - PSYCHIATRIC GENOMICS
KW - PTSD
KW - RISK-FACTORS
KW - THOUSANDS
U2 - 10.1016/j.biopsych.2021.09.020
DO - 10.1016/j.biopsych.2021.09.020
M3 - Article
C2 - 34865855
SN - 0006-3223
VL - 91
SP - 626
EP - 636
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 7
ER -