Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use.

TitleExome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use.
Publication TypeJournal Article
Year of Publication2019
AuthorsBrazel, DM, Jiang, Y, Hughey, JM, Turcot, V, Zhan, X, Gong, J, Batini, C, J Weissenkampen, D, Liu, M, Barnes, DR, Bertelsen, S, Chou, Y-L, A Erzurumluoglu, M, Faul, J, Haessler, J, Hammerschlag, AR, Hsu, C, Kapoor, M, Lai, D, Le, N, de Leeuw, C, Loukola, A, Mangino, M, Melbourne, CA, Pistis, G, Qaiser, B, Rohde, R, Shao, Y, Stringham, HM, Wetherill, L, Zhao, W, Agrawal, A, Bierut, L, Chen, C, Eaton, CB, Goate, A, Haiman, CA, Heath, AC, Iacono, WG, Martin, NG, Polderman, TJ, Reiner, A, Rice, J, Schlessinger, D, H Scholte, S, Smith, JA, Tardif, J-C, Tindle, HA, Van Der Leij, AR, Boehnke, M, Chang-Claude, J, Cucca, F, David, SP, Foroud, T, Howson, JMM, Kardia, SLR, Kooperberg, C, Laakso, M, Lettre, G, Madden, PAF, McGue, M, North, KE, Posthuma, D, Spector, T, Stram, D, Tobin, MD, Weir, DR, Kaprio, J, Abecasis, GR, Liu, DJ, Vrieze, S
Corporate AuthorsCHD Exome+ Consortium, Consortium for Genetics of Smoking Behaviour
JournalBiological Psychiatry
Volume85
Issue11
Pagination946-955
ISSN Number1873-2402
KeywordsAlcohol Drinking, Databases, Genetic, Exome, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Smoking
Abstract

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.

DOI10.1016/j.biopsych.2018.11.024
Citation Key12125
PubMed ID30679032
PubMed Central IDPMC6534468
Grant ListT32 DA017637 / DA / NIDA NIH HHS / United States
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
U01 AG009740 / AG / NIA NIH HHS / United States
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
R01 GM126479 / GM / NIGMS NIH HHS / United States
MR/N01104X/2 / MRC_ / Medical Research Council / United Kingdom
MR/N01104X/1 / MRC_ / Medical Research Council / United Kingdom
G1000861 / MRC_ / Medical Research Council / United Kingdom
U01 DK062370 / DK / NIDDK NIH HHS / United States
R01 DA037904 / DA / NIDA NIH HHS / United States
MR/S003762/1 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R21 DA040177 / DA / NIDA NIH HHS / United States
G1001799 / MRC_ / Medical Research Council / United Kingdom
G0700704 / MRC_ / Medical Research Council / United Kingdom
R01 HL119443 / HL / NHLBI NIH HHS / United States
R01 DK062370 / DK / NIDDK NIH HHS / United States
MC_PC_12010 / MRC_ / Medical Research Council / United Kingdom
R01 HG008983 / HG / NHGRI NIH HHS / United States
R01 DA042755 / DA / NIDA NIH HHS / United States
MR/S003746/1 / MRC_ / Medical Research Council / United Kingdom
S10 OD020069 / OD / NIH HHS / United States
/ / Wellcome Trust / United Kingdom
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom