Exome chip meta-analysis fine maps causal variants and elucidates the genetic architecture of rare coding variants in smoking and alcohol use
AuthorsDavid M. Brazel, Yu Jiang, Jordan M. Hughey, Valérie Turcot, Xiaowei Zhan, Jian Gong, Chiara Batini, J. Dylan Weissenkampen, MengZhen Liu, Daniel R. Barnes, Sarah Bertelsen, Yi-Ling Chou, A. Mesut Erzurumluoglu, Jessica D. Faul, Jeff Haessler, Anke R. Hammerschlag, Chris Hsu, Manav Kapoor, Dongbing Lai, Nhung Le, Christiaan A. de Leeuw, Anu Loukola, Massimo Mangino, Carl A. Melbourne, Giorgio Pistis, Beenish Qaiser, Rebecca Rohde, Yaming Shao, Heather Stringham, Leah Wetherill, Wei Zhao, Arpana Agrawal, Laura Bierut, Chu Chen, Charles B. Eaton, Alison Goate, Christopher Haiman, Andrew Heath, William G. Iacono, Nicholas G. Martin, Tinca J. Polderman, Alex Reiner, John Rice, David Schlessinger, H. Steven Scholte, Jennifer A. Smith, Jean-Claude Tardif, Hilary A. Tindle, Andries R. van der Leij, Michael Boehnke, Jenny Chang-Claude, Francesco Cucca, Sean P. David, Tatiana Foroud, Joanna M. M. Howson, Sharon L. R. Kardia, Charles Kooperberg, Markku Laakso, Guillaume Lettre, Pamela Madden, Matt McGue, Kari North, Danielle Posthuma, Timothy Spector, Daniel Stram, Martin D. Tobin, David R. Weir, Jaakko Kaprio, Gonçalo R. Abecasis, Dajiang J. Liu and Scott Vrieze
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 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 152,348-433,216, depending on the phenotype. Rare coding variation explained 1.1-2.2% of phenotypic variance, reflecting 11%-18% of the total SNP 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 3 and 10 variants for 65 loci. 20 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 GWAS loci identifies specific variants contributing to the biological etiology of substance use behavior.
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