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

David M. Brazel; Yu Jiang; Jordan M. Hughey; Valerie 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; Goncalo R. Abecasis; Dajiang J. Liu; Scott Vrieze; Praveen Surendran; Robin Young; Sune Fallgaard Nielsen; Asif Rasheed; Maria Samuel; Jukka Kontto; Markus Perola; Muriel Caslake; Anton J. M. de Craen; Stella Trompet; Maria Uria-Nickelsen; Anders Malarstig; Dermot F. Reily; Maarten Hoek; Thomas Vogt; J. Wouter Jukema; Naveed Sattar; Ian Ford; Chris J. Packard; Dewan S. Alam; Abdulla al Shafi Majumder; Emanuele Di Ange-Lantonio; Rajiv Chowdhury; Philippe Amouyel; Dominique Arveiler; Stefan Blankenberg; Jean Ferrieres; Frank Kee; Kari Kuulasmaa; Martina Mueller-Nurasyid; Giovanni Veronesi; Jarmo Virtamo; Philippe Frossard; Borge Gronne Nordestgaard; Danish Saleheen; John Danesh; Adam S. Butterworth; Victoria E. Jackson; Tibor V. Varga; Helen R. Warren; Vinicius Tragante; Ioanna Tachmazidou; Sarah E. Harris; Evangelos Evangelou; Jonathan Marten; Weihua Zhang; Elisabeth Altmaier; Jian'an Luan; Claudia Langenberg; Robert A. Scott; Hanieh Yaghootkar; Kathleen Stirrups; Stavroula Kanoni; Eirini Marouli; Fredrik Karpe; Anna F. Dominiczak; Peter Sever; Neil Poulter; Olov Rolandsson; Clemens Baumbach; Saima Afaq; John C. Chambers; Jaspal S. Kooner; Nicholas J. Wareham; Frida Renstrom; Goran Hallmans; Riccardo E. Marioni; Janie Corley; John M. Starr; Niek Verweij; Rudolf A. de Boer; Peter van der Meer; Ersin Yavas; Ilonca Vaartjes; Michiel L. Bots; Folkert W. Asselbergs; Hans J. Grabe; Henry Volzke; Matthias Nauck; Stefan Weiss; Paul D. P. Pharoah; Alison M. Dunning; Joe G. Dennis; Deborah J. Thompson; Kyriaki Michailidou; Douglas F. Easton; Antonis C. Antoniou; Jessica Tyrrell; Evelin Mihailov; Nilesh J. Samani; Kaixin Zhou; Matthew J. Neville; Andres Metspalu; Colin N. A. Palmer; Ian P. Hall; David P. Strachan; Ian J. Deary; Tim M. Frayling; Caroline Hayward; Pim van der Harst; Eleftheria Zeggini; Patricia B. Munroe; Jan-Hakan Jansson; Paul W. Franks; Panos Deloukas; Mark J. Caulfield; Louise V. Wain; EPIC-CVD Consortium

doi:10.1016/j.biopsych.2018.11.024

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

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

David M. Brazel, Yu Jiang, Jordan M. Hughey, Valerie Turcot, Xiaowei Zhan, Jian Gong, Chiara Batini, J. Dylan Weissenkampen, MengZhen Liu, Daniel R. Barnes, …

Biological psychiatry (1969), Vol.85(11), pp.946-955

01/06/2019

DOI: https://doi.org/10.1016/j.biopsych.2018.11.024

PMID: 30679032

Abstract

Life Sciences & Biomedicine

Neurosciences

Neurosciences & Neurology

Psychiatry

Science & Technology

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 similar to 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.

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Title: Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use
Creators - without role: David M. Brazel - Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA
Yu Jiang - Pennsylvania State University
Jordan M. Hughey - Pennsylvania State University
Valerie Turcot - College Station Medical Center
Xiaowei Zhan - Univ Texas Southwestern, Dept Clin Sci, Ctr Genet Host Def, Dallas, TX USA
Jian Gong - Hutchinson
Chiara Batini - University of Leicester
J. Dylan Weissenkampen - Pennsylvania State University
MengZhen Liu
Daniel R. Barnes - University of Cambridge
Sarah Bertelsen - Supreme Council Of Health
Yi-Ling Chou - Supreme Council Of Health
A. Mesut Erzurumluoglu - University of Leicester
Jessica D. Faul - Supreme Council Of Health
Jeff Haessler - Hutchinson
Anke R. Hammerschlag - University of Amsterdam
Chris Hsu - Supreme Council Of Health
Manav Kapoor - Supreme Council Of Health
Dongbing Lai - Indiana University
Nhung Le - Supreme Council Of Health
Christiaan A. de Leeuw - University of Amsterdam
Anu Loukola - University of Helsinki
Massimo Mangino
Carl A. Melbourne - University of Leicester
Giorgio Pistis - CNR, Ist Ric Genet & Biomed, Monserrato, Italy
Beenish Qaiser - University of Helsinki
Rebecca Rohde - Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA
Yaming Shao - Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA
Heather Stringham - Biostat
Leah Wetherill - Indiana University
Wei Zhao - Supreme Council Of Health
Arpana Agrawal - Supreme Council Of Health
Laura Bierut - Supreme Council Of Health
Chu Chen - Hutchinson
Charles B. Eaton - Brown University
Alison Goate - Supreme Council Of Health
Christopher Haiman - Supreme Council Of Health
Andrew Heath - Supreme Council Of Health
William G. Iacono - University of Minnesota
Nicholas G. Martin - College Station Medical Center
Tinca J. Polderman - University of Amsterdam
Alex Reiner - Hutchinson
John Rice - Supreme Council Of Health
David Schlessinger
H. Steven Scholte - University of Amsterdam
Jennifer A. Smith - Supreme Council Of Health
Jean-Claude Tardif - College Station Medical Center
Hilary A. Tindle - Vanderbilt University
Andries R. van der Leij - University of Amsterdam
Michael Boehnke - Biostat
Jenny Chang-Claude - Heidelberg
Francesco Cucca - CNR, Ist Ric Genet & Biomed, Monserrato, Italy
Sean P. David - Stanford University
Tatiana Foroud - Indiana University
Joanna M. M. Howson - University of Cambridge
Sharon L. R. Kardia - Supreme Council Of Health
Charles Kooperberg - Hutchinson
Markku Laakso
Guillaume Lettre - College Station Medical Center
Pamela Madden - Supreme Council Of Health
Matt Mcgue
Kari North - Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA
Danielle Posthuma - University of Amsterdam
Timothy Spector - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Daniel Stram
Martin D. Tobin - University of Leicester
David R. Weir - Supreme Council Of Health
Jaakko Kaprio - University of Helsinki
Goncalo R. Abecasis - Regeneron
Dajiang J. Liu - Pennsylvania State University
Scott Vrieze - University of Minnesota
Praveen Surendran
Robin Young
Daniel R. Barnes
Sune Fallgaard Nielsen
Asif Rasheed
Maria Samuel
Wei Zhao
Jukka Kontto
Markus Perola
Muriel Caslake
Anton J. M. de Craen
Stella Trompet
Maria Uria-Nickelsen
Anders Malarstig
Dermot F. Reily
Maarten Hoek
Thomas Vogt
J. Wouter Jukema
Naveed Sattar
Ian Ford
Chris J. Packard
Dewan S. Alam
Abdulla al Shafi Majumder
Emanuele Di Ange-Lantonio
Rajiv Chowdhury
Philippe Amouyel
Dominique Arveiler
Stefan Blankenberg
Jean Ferrieres
Frank Kee
Kari Kuulasmaa
Martina Mueller-Nurasyid
Giovanni Veronesi
Jarmo Virtamo
Philippe Frossard
Borge Gronne Nordestgaard
Danish Saleheen
John Danesh
Adam S. Butterworth
Joanna M. M. Howson
A. Mesut Erzurumluoglu
Victoria E. Jackson
Carl A. Melbourne
Tibor V. Varga
Helen R. Warren
Vinicius Tragante
Ioanna Tachmazidou
Sarah E. Harris
Evangelos Evangelou
Jonathan Marten
Weihua Zhang
Elisabeth Altmaier
Jian'an Luan
Claudia Langenberg
Robert A. Scott
Hanieh Yaghootkar
Kathleen Stirrups
Stavroula Kanoni
Eirini Marouli
Fredrik Karpe
Anna F. Dominiczak
Peter Sever
Neil Poulter
Olov Rolandsson
Clemens Baumbach
Saima Afaq
John C. Chambers
Jaspal S. Kooner
Nicholas J. Wareham
Frida Renstrom
Goran Hallmans
Riccardo E. Marioni
Janie Corley
John M. Starr
Niek Verweij
Rudolf A. de Boer
Peter van der Meer
Ersin Yavas
Ilonca Vaartjes
Michiel L. Bots
Folkert W. Asselbergs
Hans J. Grabe
Henry Volzke
Matthias Nauck
Stefan Weiss
Paul D. P. Pharoah
Alison M. Dunning
Joe G. Dennis
Deborah J. Thompson
Kyriaki Michailidou
Douglas F. Easton
Antonis C. Antoniou
Jessica Tyrrell
Evelin Mihailov
Nilesh J. Samani
Kaixin Zhou
Matthew J. Neville
Andres Metspalu
Colin N. A. Palmer
Ian P. Hall
David P. Strachan
Ian J. Deary
Tim M. Frayling
Caroline Hayward
Pim van der Harst
Eleftheria Zeggini
Patricia B. Munroe
Jan-Hakan Jansson
Paul W. Franks
Panos Deloukas
Mark J. Caulfield
Louise V. Wain
Martin D. Tobin
EPIC-CVD Consortium
Publication Details: Biological psychiatry (1969), Vol.85(11), pp.946-955
Publisher: Elsevier
Number of pages: 10
Grant note: DGE1255832 / National Science Foundation Graduate Research Fellowship Program; National Science Foundation (NSF) Pfizer MC_UU_00007/10 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) R01DA037904; R21DA040177; R01HG008983; R01GM126479; 5T32DA01763713 / National Human Genome Research Institute of the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) G0700704; MR/N01104X/1; MR/S003746/1; MC_UU_12015/1; G1001799; MC_PC_12010; MR/L003120/1; G1000861; MR/S003762/1; MR/N01104X/2 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) ZIAAG000675 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) ES/S008349/1 / ESRC; UK Research & Innovation (UKRI); Economic & Social Research Council (ESRC) National Institute on Drug Abuse; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA) National Science Foundation Graduate Research Fellowship; National Science Foundation (NSF) European Union Innovative Medicines Initiative (IMI)
Identifiers: 9938740208331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article