Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use.
Alcohol Drinking
/ genetics
Databases, Genetic
Exome
Genetic Predisposition to Disease
/ genetics
Genetic Variation
/ physiology
Genome-Wide Association Study
/ statistics & numerical data
Genotype
Humans
Oligonucleotide Array Sequence Analysis
/ statistics & numerical data
Phenotype
Polymorphism, Single Nucleotide
/ genetics
Smoking
/ genetics
Alcohol
Behavioral genetics
GWAS
Heritability
Nicotine
Tobacco
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
received:
15
09
2017
revised:
05
11
2018
accepted:
29
11
2018
pubmed:
27
1
2019
medline:
14
4
2020
entrez:
26
1
2019
Statut:
ppublish
Résumé
Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
Sections du résumé
BACKGROUND
Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.
METHODS
We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.
RESULTS
Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.
CONCLUSIONS
Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
Identifiants
pubmed: 30679032
pii: S0006-3223(18)32056-0
doi: 10.1016/j.biopsych.2018.11.024
pmc: PMC6534468
mid: NIHMS1519259
pii:
doi:
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
946-955Subventions
Organisme : NIDA NIH HHS
ID : T32 DA017637
Pays : United States
Organisme : Medical Research Council
ID : MR/L003120/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U01 AG009740
Pays : United States
Organisme : British Heart Foundation
ID : RG/13/13/30194
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM126479
Pays : United States
Organisme : Medical Research Council
ID : MR/N01104X/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N01104X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1000861
Pays : United Kingdom
Organisme : NIDA NIH HHS
ID : R01 DA037904
Pays : United States
Organisme : Medical Research Council
ID : MR/S003762/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : NIAAA NIH HHS
ID : R37 AA009367
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_12015/1
Pays : United Kingdom
Organisme : NIDA NIH HHS
ID : R21 DA040177
Pays : United States
Organisme : Medical Research Council
ID : G1001799
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0700704
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL119443
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062370
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_12010
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : R01 HG008983
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA042755
Pays : United States
Organisme : Medical Research Council
ID : MR/S003746/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : U01 DK062370
Pays : United States
Organisme : NIH HHS
ID : S10 OD020069
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K026992/1
Pays : United Kingdom
Investigateurs
Praveen Surendran
(P)
Robin Young
(R)
Daniel R Barnes
(DR)
Sune Fallgaard Nielsen
(SF)
Asif Rasheed
(A)
Maria Samuel
(M)
Wei Zhao
(W)
Jukka Kontto
(J)
Markus Perola
(M)
Muriel Caslake
(M)
Anton J M de Craen
(AJM)
Stella Trompet
(S)
Maria Uria-Nickelsen
(M)
Anders Malarstig
(A)
Dermot F Reily
(DF)
Maarten Hoek
(M)
Thomas Vogt
(T)
J Wouter Jukema
(JW)
Naveed Sattar
(N)
Ian Ford
(I)
Chris J Packard
(CJ)
Dewan S Alam
(DS)
Abdulla Al Shafi Majumder
(AAS)
Emanuele Di Angelantonio
(E)
Rajiv Chowdhury
(R)
Philippe Amouyel
(P)
Dominique Arveiler
(D)
Stefan Blankenberg
(S)
Jean Ferrières
(J)
Frank Kee
(F)
Kari Kuulasmaa
(K)
Martina Müller-Nurasyid
(M)
Giovanni Veronesi
(G)
Jarmo Virtamo
(J)
None Epic-Cvd Consortium
Philippe Frossard
(P)
Børge Grønne Nordestgaard
(BG)
Danish Saleheen
(D)
John Danesh
(J)
Adam S Butterworth
(AS)
Joanna M M Howson
(JMM)
A Mesut Erzurumluoglu
(AM)
Victoria E Jackson
(VE)
Carl A Melbourne
(CA)
Tibor V Varga
(TV)
Helen R Warren
(HR)
Vinicius Tragante
(V)
Ioanna Tachmazidou
(I)
Sarah E Harris
(SE)
Evangelos Evangelou
(E)
Jonathan Marten
(J)
Weihua Zhang
(W)
Elisabeth Altmaier
(E)
Jian'an Luan
(J)
Claudia Langenberg
(C)
Robert A Scott
(RA)
Hanieh Yaghootkar
(H)
Kathleen Stirrups
(K)
Stavroula Kanoni
(S)
Eirini Marouli
(E)
Fredrik Karpe
(F)
Anna F Dominiczak
(AF)
Peter Sever
(P)
Neil Poulter
(N)
Olov Rolandsson
(O)
Clemens Baumbach
(C)
Saima Afaq
(S)
John C Chambers
(JC)
Jaspal S Kooner
(JS)
Nicholas J Wareham
(NJ)
Frida Renström
(F)
Göran Hallmans
(G)
Riccardo E Marioni
(RE)
Janie Corley
(J)
John M Starr
(JM)
Niek Verweij
(N)
Rudolf A de Boer
(RA)
Peter van der Meer
(P)
Ersin Yavas
(E)
Ilonca Vaartjes
(I)
Michiel L Bots
(ML)
Folkert W Asselbergs
(FW)
Hans J Grabe
(HJ)
Henry Völzke
(H)
Matthias Nauck
(M)
Stefan Weiss
(S)
Paul D P Pharoah
(PDP)
Alison M Dunning
(AM)
Joe G Dennis
(JG)
Deborah J Thompson
(DJ)
Kyriaki Michailidou
(K)
Douglas F Easton
(DF)
Antonis C Antoniou
(AC)
Jessica Tyrrell
(J)
Evelin Mihailov
(E)
Nilesh J Samani
(NJ)
Kaixin Zhou
(K)
Matthew J Neville
(MJ)
Andres Metspalu
(A)
Colin N A Palmer
(CNA)
Ian P Hall
(IP)
David P Strachan
(DP)
Ian J Deary
(IJ)
Tim M Frayling
(TM)
Caroline Hayward
(C)
Pim van der Harst
(P)
Eleftheria Zeggini
(E)
None Understanding Society Scientific Group
Patricia B Munroe
(PB)
Jan-Håkan Jansson
(JH)
Paul W Franks
(PW)
Panos Deloukas
(P)
Mark J Caulfield
(MJ)
Louise V Wain
(LV)
Martin D Tobin
(MD)
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Références
PLoS One. 2014 May 07;9(5):e96753
pubmed: 24804708
Nat Rev Genet. 2018 Aug;19(8):491-504
pubmed: 29844615
Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1057-1071
pubmed: 27473937
Addict Biol. 2015 May;20(3):594-604
pubmed: 24735490
Mol Psychiatry. 2016 May;21(5):594-600
pubmed: 26952864
Trends Neurosci. 2016 Dec;39(12):851-861
pubmed: 27871728
Psychol Med. 2004 Oct;34(7):1251-61
pubmed: 15697051
Am J Hum Genet. 2011 Jul 15;89(1):82-93
pubmed: 21737059
J Hum Genet. 2013 Mar;58(3):178-9
pubmed: 23324950
Alcohol Res Health. 2007;30(1):22-7
pubmed: 17718397
Am J Hum Genet. 2008 Sep;83(3):311-21
pubmed: 18691683
Am J Med Genet B Neuropsychiatr Genet. 2014 Dec;165B(8):673-83
pubmed: 25270064
Nat Genet. 2014 Feb;46(2):200-4
pubmed: 24336170
Nature. 2017 Feb 9;542(7640):186-190
pubmed: 28146470
Pharmacogenet Genomics. 2013 Aug;23(8):395-402
pubmed: 23778322
Biol Psychiatry. 2011 Sep 15;70(6):528-36
pubmed: 21683344
Nat Genet. 2016 Oct;48(10):1279-83
pubmed: 27548312
Hum Mol Genet. 2012 Feb 1;21(3):647-55
pubmed: 22042774
Mol Psychiatry. 2015 Nov;20(11):1467-78
pubmed: 25450229
Mol Psychiatry. 2016 May;21(5):601-7
pubmed: 26239294
Nat Genet. 2015 Mar;47(3):291-5
pubmed: 25642630
Nat Genet. 2015 Nov;47(11):1236-41
pubmed: 26414676
Nucleic Acids Res. 2014 Jan;42(Database issue):D756-63
pubmed: 24259432
Behav Genet. 2013 Mar;43(2):97-107
pubmed: 23362009
J Pharmacol Exp Ther. 2014 Mar;348(3):410-20
pubmed: 24385388
Psychophysiology. 2014 Dec;51(12):1309-20
pubmed: 25387710
Nat Genet. 2015 Jul;47(7):702-9
pubmed: 25985137
Pharmacogenet Genomics. 2014 Feb;24(2):118-28
pubmed: 24305170
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Am J Hum Genet. 2014 Apr 3;94(4):559-73
pubmed: 24702953
Biostatistics. 2012 Sep;13(4):762-75
pubmed: 22699862
Genet Epidemiol. 2015 Dec;39(8):619-23
pubmed: 26394715
Nat Genet. 2010 Apr;42(4):348-54
pubmed: 20208533
Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14372-14377
pubmed: 27911795
Psychol Bull. 2006 Jul;132(4):607-21
pubmed: 16822169
Behav Genet. 2011 Jul;41(4):459-75
pubmed: 21153693
J Carcinog Mutagen. 2014;5:
pubmed: 25621181
Nat Genet. 2010 May;42(5):441-7
pubmed: 20418890
Am J Psychiatry. 2011 Oct;168(10):1041-9
pubmed: 21890791
J Subst Abuse. 1990;2(1):39-50
pubmed: 2136102
Biol Psychiatry. 2014 May 15;75(10):783-9
pubmed: 24094508
Behav Genet. 2005 Jul;35(4):397-406
pubmed: 15971021
Hum Mol Genet. 2014 Feb 1;23(3):810-9
pubmed: 24057674
PLoS Genet. 2010 Aug 05;6(8):
pubmed: 20700436
Alcohol Res Health. 2007;30(1):5-13
pubmed: 17718394
Nat Genet. 2018 Nov;50(11):1505-1513
pubmed: 30297969
Lancet. 2002 Nov 2;360(9343):1347-60
pubmed: 12423980
Psychophysiology. 2014 Dec;51(12):1300-8
pubmed: 25387709
Nat Genet. 2018 May;50(5):737-745
pubmed: 29700474
Nat Genet. 2010 May;42(5):448-53
pubmed: 20418888
PLoS Genet. 2018 Jul 17;14(7):e1007452
pubmed: 30016313
Neuropsychopharmacology. 2010 Nov;35(12):2392-402
pubmed: 20736995
Mol Psychiatry. 2017 Sep;22(9):1359-1367
pubmed: 28485404
Nat Genet. 2016 Mar;48(3):314-7
pubmed: 26854916
Neurosci Biobehav Rev. 2010 Nov;35(2):157-71
pubmed: 19914287