WashU weekly Neuroscience publications

Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use
(2019) Biological Psychiatry, . Article in Press. 

Brazel, D.M.^{a b} , Jiang, Y.^c , Hughey, J.M.^c , Turcot, V.^{e f} , Zhan, X.^g , Gong, J.^h , Batini, C.^k , Weissenkampen, J.D.^c , Liu, M.^o , Surendran, P.^ao , Young, R.^ao , Barnes, D.R.^{l ao} , Nielsen, S.F.^ao , Rasheed, A.^ao , Samuel, M.^ao , Zhao, W.^{s ao} , Kontto, J.^ao , Perola, M.^ao , Caslake, M.^ao , de Craen, A.J.M.^ao , Trompet, S.^ao , Uria-Nickelsen, M.^ao , Malarstig, A.^ao , Reily, D.F.^ao , Hoek, M.^ao , Vogt, T.^ao , Jukema, J.W.^ao , Sattar, N.^ao , Ford, I.^ao , Packard, C.J.^ao , Alam, D.S.^ao , Majumder, A.A.S.^ao , Di Angelantonio, E.^ao , Chowdhury, R.^ao , Amouyel, P.^ao , Arveiler, D.^ao , Blankenberg, S.^ao , Ferrières, J.^ao , Kee, F.^ao , Kuulasmaa, K.^ao , Müller-Nurasyid, M.^ao , Veronesi, G.^ao , Virtamo, J.^ao , EPIC-CVD Consortium^ao , Frossard, P.^ao , Nordestgaard, B.G.^ao , Saleheen, D.^ao , Danesh, J.^ao , Butterworth, A.S.^ao , Howson, J.M.M.^{l ao} , Erzurumluoglu, A.M.^{k ap} , Jackson, V.E.^ap , Melbourne, C.A.^{k ap} , Varga, T.V.^ap , Warren, H.R.^ap , Tragante, V.^ap , Tachmazidou, I.^ap , Harris, S.E.^ap , Evangelou, E.^ap , Marten, J.^ap , Zhang, W.^ap , Altmaier, E.^ap , Luan, J.^ap , Langenberg, C.^ap , Scott, R.A.^ap , Yaghootkar, H.^ap , Stirrups, K.^ap , Kanoni, S.^ap , Marouli, E.^ap , Karpe, F.^ap , Dominiczak, A.F.^ap , Sever, P.^ap , Poulter, N.^ap , Rolandsson, O.^ap , Baumbach, C.^ap , Afaq, S.^ap , Chambers, J.C.^ap , Kooner, J.S.^ap , Wareham, N.J.^ap , Renström, F.^ap , Hallmans, G.^ap , Marioni, R.E.^ap , Corley, J.^ap , Starr, J.M.^ap , Verweij, N.^ap , de Boer, R.A.^ap , van der Meer, P.^ap , Yavas, E.^ap , Vaartjes, I.^ap , Bots, M.L.^ap , Asselbergs, F.W.^ap , Grabe, H.J.^ap , Völzke, H.^ap , Nauck, M.^ap , Weiss, S.^ap , Pharoah, P.D.P.^ap , Dunning, A.M.^ap , Dennis, J.G.^ap , Thompson, D.J.^ap , Michailidou, K.^ap , Easton, D.F.^ap , Antoniou, A.C.^ap , Tyrrell, J.^ap , Mihailov, E.^ap , Samani, N.J.^ap , Zhou, K.^ap , Neville, M.J.^ap , Metspalu, A.^ap , Palmer, C.N.A.^ap , Hall, I.P.^ap , Strachan, D.P.^ap , Deary, I.J.^ap , Frayling, T.M.^ap , Hayward, C.^ap , van der Harst, P.^ap , Zeggini, E.^ap , Understanding Society Scientific Group^ap , Munroe, P.B.^ap , Jansson, J.-H.^ap , Franks, P.W.^ap , Deloukas, P.^ap , Caulfield, M.J.^ap , Wain, L.V.^ap , Tobin, M.D.^{k ap} , Bertelsen, S.^p , Chou, Y.-L.^ah , Faul, J.D.^r , Haessler, J.^h , Hammerschlag, A.R.^u , Hsu, C.^y , Kapoor, M.^p , Lai, D.^aa , Le, N.^ab , de Leeuw, C.A.^u , Loukola, A.^{ac ad} , Mangino, M.^{m n} , Pistis, G.^af , Qaiser, B.^{ac ad} , Rohde, R.^ag , Shao, Y.^ag , Stringham, H.^t , Wetherill, L.^aa , Agrawal, A.^ah , Bierut, L.^ah , Chen, C.^{h i j} , Eaton, C.B.^aj , Goate, A.^p , Haiman, C.^y , Heath, A.^ah , Iacono, W.G.^o , Martin, N.G.^ak , Polderman, T.J.^u , Reiner, A.^{h i} , Rice, J.^{ah ai} , Schlessinger, D.^al , Scholte, H.S.^{w x} , Smith, J.A.^s , Tardif, J.-C.^{e f} , Tindle, H.A.^am , van der Leij, A.R.^{w x} , Boehnke, M.^t , Chang-Claude, J.^an , Cucca, F.^af , David, S.P.^z , Foroud, T.^aa , Kardia, S.L.R.^s , Kooperberg, C.^h , Laakso, M.^ae , Lettre, G.^{e f} , Madden, P.^ah , McGue, M.^o , North, K.^ag , Posthuma, D.^{u v} , Spector, T.^m , Stram, D.^y , Weir, D.R.^r , Kaprio, J.^{ac ad} , Abecasis, G.R.^{q t} , Liu, D.J.^d , Vrieze, S.^o , CHD Exome+ Consortium^aq , Consortium for Genetics of Smoking Behaviour^aq

^a Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, United States
^b Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, United States
^c Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, United States
^d Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, United States
^e Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
^f Montreal Heart Institute, Montreal, Quebec, Canada
^g Department of Clinical Science, Center for Genetics of Host Defense, University of Texas Southwestern, Dallas, TX, United States
^h Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
ⁱ Department of Epidemiology, Head and Neck Surgery Center, University of Washington, Seattle, WA, United States
^j Department of Otolaryngology, Head and Neck Surgery Center, University of Washington, Seattle, WA, United States
^k Department of Health Sciences, University of Leicester, Leicester, United Kingdom
^l Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
^m Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
ⁿ National Institute for Health Research Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust, London, United Kingdom
^o Department of Psychology, University of Minnesota, Minneapolis, MN, United States
^p Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^q Regeneron Pharmaceuticals, Tarrytown, NY, United States
^r Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
^s Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States
^t Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, United States
^u Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, Netherlands
^v Department of Clinical Genetics, VU University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
^w Department of Psychology, University of Amsterdam, Amsterdam, Netherlands
^x Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, Netherlands
^y Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^z Department of Medicine, Stanford University, Stanford, CA, United States
^aa Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, India
^ab Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States
^ac Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
^ad Department of Public Health, University of Helsinki, Helsinki, Finland
^ae Department of Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
^af Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy
^ag Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^ah Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^ai Department of Mathematics, Washington University in St. Louis, St. Louis, MO, United States
^aj Department of Family Medicine, Brown University, Providence, RI, United States
^ak Queensland Institute for Medical Research, Brisbane, Australia
^al National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
^am Department of Medicine, Vanderbilt University, Nashville, TN, United States
^an Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany

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. © 2018 Society of Biological Psychiatry

Author Keywords
Alcohol;  Behavioral genetics;  GWAS;  Heritability;  Nicotine;  Tobacco

Document Type: Article in Press
Publication Stage: Article in Press
Source: Scopus