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Biol Psychiatry. 2018 Dec 6. pii: S0006-3223(18)32056-0. doi: 10.1016/j.biopsych.2018.11.024. [Epub ahead of print]

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

Author information

1
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado; Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado.
2
Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.
3
Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
4
Department of Clinical Science, Center for Genetics of Host Defense, University of Texas Southwestern, Dallas, Texas.
5
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
6
Department of Health Sciences, University of Leicester, Leicester, United Kingdom.
7
Department of Psychology, University of Minnesota, Minneapolis, Minnesota.
8
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
9
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.
10
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
11
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan.
12
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.
13
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
14
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
15
Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
16
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
17
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, United Kingdom.
18
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy.
19
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
20
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
21
Department of Epidemiology, University of Michigan, Ann Arbor, Michigan.
22
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, Head and Neck Surgery Center, University of Washington, Seattle, Washington; Department of Otolaryngology, Head and Neck Surgery Center, University of Washington, Seattle, Washington.
23
Department of Family Medicine, Brown University, Providence, Rhode Island.
24
Queensland Institute for Medical Research, Brisbane, Australia.
25
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, Head and Neck Surgery Center, University of Washington, Seattle, Washington.
26
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri; Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri.
27
National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
28
Department of Psychology, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.
29
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
30
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
31
Department of Medicine, Stanford University, Stanford, California.
32
Department of Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
33
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, the Netherlands; Department of Clinical Genetics, VU University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
34
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
35
Regeneron Pharmaceuticals, Tarrytown, New York; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
36
Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania. Electronic address: dajiang.liu@psu.edu.
37
Department of Psychology, University of Minnesota, Minneapolis, Minnesota. Electronic address: vrieze@umn.edu.

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.

KEYWORDS:

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

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