Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information.
GWAS
Genetics
Heritability
PTSD
PheWAS
Trauma
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 04 2022
01 04 2022
Historique:
received:
28
04
2021
revised:
25
08
2021
accepted:
21
09
2021
pubmed:
7
12
2021
medline:
6
4
2022
entrez:
6
12
2021
Statut:
ppublish
Résumé
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). 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 34865855
pii: S0006-3223(21)01632-2
doi: 10.1016/j.biopsych.2021.09.020
pmc: PMC8917986
mid: NIHMS1763555
pii:
doi:
Types de publication
Journal Article
Meta-Analysis
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
626-636Subventions
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : RRD VA
ID : IK2 RX002922
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH091391
Pays : United States
Organisme : BLRD VA
ID : I21 BX005872
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH109539
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH106595
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG064955
Pays : United States
Organisme : NIMH NIH HHS
ID : K23 MH117278
Pays : United States
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : BLRD VA
ID : I01 BX004312
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA017846
Pays : United States
Organisme : NIMH NIH HHS
ID : K01 MH118467
Pays : United States
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG022381
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG050595
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2021 Society of Biological Psychiatry. All rights reserved.
Références
Transl Psychiatry. 2018 Oct 2;8(1):205
pubmed: 30279410
Nat Genet. 2019 Sep;51(9):1339-1348
pubmed: 31427789
Eur J Psychotraumatol. 2017 Oct 27;8(sup5):1353383
pubmed: 29075426
Genomics Inform. 2016 Dec;14(4):173-180
pubmed: 28154508
Nat Genet. 2021 Feb;53(2):195-204
pubmed: 33462486
BMC Bioinformatics. 2008 Dec 16;9:540
pubmed: 19087329
G3 (Bethesda). 2011 Nov;1(6):457-70
pubmed: 22384356
Am J Physiol Cell Physiol. 2020 Feb 1;318(2):C272-C281
pubmed: 31747314
PLoS Comput Biol. 2015 Apr 17;11(4):e1004219
pubmed: 25885710
Nat Commun. 2020 Oct 14;11(1):5180
pubmed: 33057013
Oncotarget. 2017 May 23;8(34):56684-56697
pubmed: 28915622
Nat Genet. 2017 Jul;49(7):1120-1125
pubmed: 28553958
Biol Psychiatry. 2017 Jun 15;81(12):1023-1029
pubmed: 28117048
Nat Genet. 2004 Jan;36(1):69-76
pubmed: 14647276
Biol Psychiatry Cogn Neurosci Neuroimaging. 2018 Nov;3(11):959-967
pubmed: 30409390
Arch Gen Psychiatry. 2012 Mar;69(3):293-9
pubmed: 22393221
PLoS Pathog. 2015 Mar 12;11(3):e1004726
pubmed: 25763818
Nat Methods. 2012 Apr 27;9(5):459-62
pubmed: 22543379
Cell. 2019 Dec 12;179(7):1469-1482.e11
pubmed: 31835028
Psychol Med. 2017 Oct;47(13):2260-2274
pubmed: 28385165
Curr Psychiatry Rep. 2010 Aug;12(4):313-26
pubmed: 20549395
Nat Commun. 2019 Jul 19;10(1):3222
pubmed: 31324783
Hum Mol Genet. 2020 Sep 30;29(R1):R10-R18
pubmed: 32568380
Front Mol Neurosci. 2019 Jun 25;12:152
pubmed: 31316346
Nat Genet. 2015 Mar;47(3):291-5
pubmed: 25642630
Nat Genet. 2018 Jul;50(7):906-908
pubmed: 29892013
Nat Genet. 2021 Feb;53(2):174-184
pubmed: 33510476
Bioinformatics. 2020 Feb 1;36(3):930-933
pubmed: 31393554
Biol Mood Anxiety Disord. 2012 May 18;2:9
pubmed: 22738125
Nat Genet. 2018 Jul;50(7):920-927
pubmed: 29942085
J Trauma Stress. 2007 Feb;20(1):3-13
pubmed: 17345644
Nat Genet. 2019 Jan;51(1):63-75
pubmed: 30478444
Psychol Med. 2016 Jan;46(2):327-43
pubmed: 26511595
Science. 2020 Sep 11;369(6509):1318-1330
pubmed: 32913098
Transl Psychiatry. 2017 Nov 30;7(11):1265
pubmed: 29187748
Nat Commun. 2019 Oct 8;10(1):4558
pubmed: 31594949
Int J Mol Sci. 2019 Nov 04;20(21):
pubmed: 31689918
Nat Genet. 2019 Apr;51(4):584-591
pubmed: 30926966
Psychol Bull. 2007 Mar;133(2):183-204
pubmed: 17338596
J Consult Clin Psychol. 2000 Oct;68(5):748-66
pubmed: 11068961
Neuropsychopharmacology. 2015 Sep;40(10):2287-97
pubmed: 25904361
Epidemiology. 2014 Sep;25(5):749-61
pubmed: 25000145
Nat Rev Neurosci. 2012 Nov;13(11):769-87
pubmed: 23047775
Nat Genet. 2017 Jul;49(7):1107-1112
pubmed: 28530673
Nat Protoc. 2012 Feb 16;7(3):500-7
pubmed: 22343431
PLoS One. 2013 Aug 19;8(8):e71494
pubmed: 23977056
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
PLoS One. 2014 Sep 03;9(9):e103653
pubmed: 25184336
Biopreserv Biobank. 2015 Oct;13(5):311-9
pubmed: 26484571
Bioinformatics. 2017 Jan 15;33(2):272-279
pubmed: 27663502
Hum Mol Genet. 2019 Nov 15;28(22):3853-3865
pubmed: 31518406
PLoS Genet. 2019 Apr 5;15(4):e1008009
pubmed: 30951530
J Psychiatr Res. 2009 May;43(8):809-17
pubmed: 19091328
Transl Psychiatry. 2020 Jan 27;10(1):38
pubmed: 32066696
Histochem Cell Biol. 2019 May;151(5):385-394
pubmed: 30357511
Nature. 2009 Nov 12;462(7270):213-7
pubmed: 19907493
Am J Psychiatry. 2018 Jan 1;175(1):15-27
pubmed: 28969442
Nat Genet. 2018 Feb;50(2):229-237
pubmed: 29292387
Nat Neurosci. 2019 Sep;22(9):1394-1401
pubmed: 31358989
Am J Psychiatry. 2002 Oct;159(10):1675-81
pubmed: 12359672
Nat Genet. 2006 Aug;38(8):904-9
pubmed: 16862161
Bioinformatics. 2010 Sep 15;26(18):2336-7
pubmed: 20634204
Nat Neurosci. 2021 Jan;24(1):24-33
pubmed: 33349712
Bioinformatics. 2016 May 15;32(10):1479-85
pubmed: 26708335
Can J Psychiatry. 2014 Sep;59(9):460-7
pubmed: 25565692
Perspect Psychol Sci. 2013 Nov;8(6):651-62
pubmed: 26173229
Cell Rep. 2020 Jun 2;31(9):107716
pubmed: 32492425
Mol Psychiatry. 2018 Mar;23(3):666-673
pubmed: 28439101
Hum Brain Mapp. 2017 Jan;38(1):541-560
pubmed: 27647695
Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Jan 13;2(4):363-371
pubmed: 28435932
Nat Rev Dis Primers. 2015 Oct 08;1:15057
pubmed: 27189040