SynthesisBiological psychiatry2019
Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use.
Abstract readMeta-Analysis
In one paragraph
Synthesis in Biological psychiatry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers, 3 of them syntheses that pooled it.
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49citing papers in PubMed, 3 pooled it
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What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
49 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.Nature human behaviour · 2024Pooled it
- Assessment of the Association of D2 Dopamine Receptor Gene and Reported Allele Frequencies With Alcohol Use Disorders: A Systematic Review and Meta-analysis.JAMA network open · 2019Pooled it
- Methods for the Analysis and Interpretation for Rare Variants Associated with Complex Traits.Current protocols in human genetics · 2019Pooled it
- Genome-wide association study of delay discounting identifies 11 loci and reveals transdiagnostic associations across mental and physical health.Molecular psychiatry · 2026Article
- Genome-wide association studies of lifetime and frequency of cannabis use in 131,895 individuals.Molecular psychiatry · 2026Article
- Genetic and environmental influences on alcohol consumption in middle to late life.Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors · 2025Article
- Shared biological pathways linking ADHD and cortisol variability are related to externalizing behaviors.Psychoneuroendocrinology · 2025Article
- Unraveling time-dependent genetic components underlying alcohol response.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Next-generation biomarkers for alcohol consumption and alcohol use disorder diagnosis, prognosis, and treatment: A critical review.Alcohol, clinical & experimental research · 2025Review
- The increasing authorship trend in neuroscience: A scientometric analysis across 11 countries.IBRO neuroscience reports · 2024Article
- A multi-ancestry cerebral cortex transcriptome-wide association study identifies genes associated with smoking behaviors.Molecular psychiatry · 2024Article
- Whole exome sequencing analysis identifies genes for alcohol consumption.Nature communications · 2024Article
- Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders.Molecular psychiatry · 2024Article
- A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.EBioMedicine · 2024Article
- Article
- Machine Learning of Functional Connectivity to Biotype Alcohol and Nicotine Use Disorders.Biological psychiatry. Cognitive neuroscience and neuroimaging · 2024Article
- Analysis of the brain transcriptome for substance-associated genes: An update on large-scale genome-wide association studies.Addiction biology · 2023Article
- The collaborative study on the genetics of alcoholism: Genetics.Genes, brain, and behavior · 2023Review
- Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes.medRxiv : the preprint server for health sciences · 2023Article
- Rare coding variants in CHRNB2 reduce the likelihood of smoking.Nature genetics · 2023Article
Corrections and comments
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Authors and funding
73 authors.
David M BrazelInstitute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado; Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado.
Yu JiangDepartment of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.
Jordan M HugheyDepartment of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.
Valérie TurcotDepartment of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
Xiaowei ZhanDepartment of Clinical Science, Center for Genetics of Host Defense, University of Texas Southwestern, Dallas, Texas.
Jian GongPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Chiara BatiniDepartment of Health Sciences, University of Leicester, Leicester, United Kingdom.
J Dylan WeissenkampenDepartment of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.
MengZhen LiuDepartment of Psychology, University of Minnesota, Minneapolis, Minnesota.
CHD Exome+ Consortium
Consortium for Genetics of Smoking Behaviour
Daniel R BarnesDepartment of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Sarah BertelsenDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.
Yi-Ling ChouDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
A Mesut ErzurumluogluDepartment of Health Sciences, University of Leicester, Leicester, United Kingdom.
Jessica D FaulSurvey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan.
Jeff HaesslerPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Anke R HammerschlagDepartment of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.
Chris HsuDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Manav KapoorDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.
Dongbing LaiDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Nhung LeDepartment of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois.
Christiaan A de LeeuwDepartment of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.
Anu LoukolaInstitute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
Massimo ManginoDepartment 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.
Carl A MelbourneDepartment of Health Sciences, University of Leicester, Leicester, United Kingdom.
Giorgio PistisIstituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy.
Beenish QaiserInstitute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
Rebecca RohdeDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Yaming ShaoDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Heather StringhamDepartment of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
Leah WetherillDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Wei ZhaoDepartment of Epidemiology, University of Michigan, Ann Arbor, Michigan.
Arpana AgrawalDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Laura BierutDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Chu ChenPublic 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.
Charles B EatonDepartment of Family Medicine, Brown University, Providence, Rhode Island.
Alison GoateDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.
Christopher HaimanDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Andrew HeathDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
William G IaconoDepartment of Psychology, University of Minnesota, Minneapolis, Minnesota.
Nicholas G MartinQueensland Institute for Medical Research, Brisbane, Australia.
Tinca J PoldermanDepartment of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, the Netherlands.
Alex ReinerPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, Head and Neck Surgery Center, University of Washington, Seattle, Washington.
John RiceDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri; Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri.
David SchlessingerNational Institute on Aging, National Institutes of Health, Bethesda, Maryland.
H Steven ScholteDepartment of Psychology, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.
Jennifer A SmithDepartment of Epidemiology, University of Michigan, Ann Arbor, Michigan.
Jean-Claude TardifDepartment of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
Hilary A TindleDepartment of Medicine, Vanderbilt University, Nashville, Tennessee.
Andries R van der LeijDepartment of Psychology, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, the Netherlands.
Michael BoehnkeDepartment of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
Jenny Chang-ClaudeDivision of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
Francesco CuccaIstituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy.
Sean P DavidDepartment of Medicine, Stanford University, Stanford, California.
Tatiana ForoudDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
Joanna M M HowsonDepartment of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Sharon L R KardiaDepartment of Epidemiology, University of Michigan, Ann Arbor, Michigan.
Charles KooperbergPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Markku LaaksoDepartment of Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Guillaume LettreDepartment of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
Pamela MaddenDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri.
Matt McGueDepartment of Psychology, University of Minnesota, Minneapolis, Minnesota.
Kari NorthDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Danielle PosthumaDepartment 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.
Timothy SpectorDepartment of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Daniel StramDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Martin D TobinDepartment of Health Sciences, University of Leicester, Leicester, United Kingdom.
David R WeirSurvey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan.
Jaakko KaprioInstitute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland.
Gonçalo R AbecasisRegeneron Pharmaceuticals, Tarrytown, New York; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
Dajiang J LiuInstitute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania. Electronic address: dajiang.liu@psu.edu.
Scott VriezeDepartment of Psychology, University of Minnesota, Minneapolis, Minnesota. Electronic address: vrieze@umn.edu.
Funding
HRS Yrs29-34: Y33 SSA CoFundingU01AG009740 · NIA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Jessica Faul, KENNETH M LANGA · 1990 to 2026
$555.8MIdentifying Genes for Type 2 Diabetes: FUSIONU01DK062370 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BOEHNKE, MICHAEL L, SCOTT, LAURA J. · 2009 to 2021
$11.6MThe Effects of Cannabis Legalization and Persistent Use: A Longitudinal Study of Two Twin CohortsR01DA042755 · NIDA · UNIVERSITY OF COLORADO DENVER · PI Jarrod Martin Ellingson, SOO H RHEE · 2017 to 2026
$9.9MIdentifying Genes for Type 2 Diabetes:FUSIONR01DK062370 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BOEHNKE, MICHAEL L, SCOTT, LAURA J. · 2003 to 2025
$6.7MAging-related Traits and Disease Risk Factors in a Sardinian Population CohortZIAAG000675 · NIA · NATIONAL INSTITUTE ON AGING · PI GOROSPE, MYRIAM · 2009 to 2021
$5.7MAdolescent drinking and midlife outcomes: A prospective cotwin control studyR37AA009367 · NIAAA · UNIVERSITY OF MINNESOTA · PI MCGUE, MATTHEW K. · 2016 to 2024
$5.4MResearch Training-Genetics of Substance AbuseT32DA017637 · NIDA · UNIVERSITY OF COLORADO AT BOULDER · PI STITZEL, JERRY A · 2004 to 2023
$5.3MGenetic Association Meta-Analyses of Smoking and Drinking for the Sequencing AgeR01DA037904 · NIDA · UNIVERSITY OF MINNESOTA · PI VRIEZE, SCOTT IAN · 2015 to 2019
$2.4MGenetic Mechanisms of Arteriosclerosis in Hypertensive SibshipsR01HL119443 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KARDIA, SHARON L · 2014 to 2017
$2.1MMethod to Enhance the Rare Variant Genetic Architecture Analysis in Meta-AnalysesR01HG008983 · NHGRI · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI LIU, DAJIANG · 2016 to 2019
$1.6MTools for integrative genomics and disease association study for the X chromosomeR01GM126479 · NIGMS · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI LIU, DAJIANG · 2018 to 2021
$1.2MFHCRC High-Performance Computing ClusterS10OD020069 · OD · FRED HUTCHINSON CANCER RESEARCH CENTER · PI KOOPERBERG, CHARLES L · 2015 to 2015
$600kBritish Heart Foundation RG/13/13/30194Cancer Research UK 10119Medical Research Council G0700704Medical Research Council G1000861Medical Research Council G1001799Medical Research Council MC_PC_12010Medical Research Council MC_PC_17228Medical Research Council MC_QA137853Medical Research Council MC_UU_00007/10Medical Research Council MC_UU_12015/1Medical Research Council MR/K026992/1Medical Research Council MR/L003120/1Medical Research Council MR/N01104X/1Medical Research Council MR/N01104X/2Medical Research Council MR/S003746/1Medical Research Council MR/S003762/1NHGRI NIH HHS R01 HG008983NHLBI NIH HHS R01 HL119443NIAAA NIH HHS R37 AA009367NIA NIH HHS U01 AG009740NIDA NIH HHS R01 DA037904NIDA NIH HHS R01 DA042755NIDA NIH HHS R21 DA040177NIDA NIH HHS T32 DA017637NIDDK NIH HHS R01 DK062370NIDDK NIH HHS U01 DK062370NIGMS NIH HHS R01 GM126479NIH HHS S10 OD020069Wellcome Trust 212945/Z/18/Z
Abstract
backgroundSmoking 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.
methodsWe 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.
resultsMeta-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.
conclusionsRare 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.
Indexed as
ExomeAlcohol DrinkingDatabases, GeneticGenetic Predisposition to DiseaseGenetic VariationGenome-Wide Association StudyGenotypeHumansOligonucleotide Array Sequence AnalysisPhenotypePolymorphism, Single NucleotideSmokingAlcoholBehavioral geneticsGWASHeritabilityNicotineTobacco
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