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

CHD Exome+ Consortium, Consortium for Genetics of Smoking Behaviour

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
JournalBiological Psychiatry
DOIs
Publication statusAccepted/In press - 6 Dec 2018

Fingerprint

Exome
Meta-Analysis
Smoking
Alcohols
Phenotype
Genotype
Genome-Wide Association Study
Tobacco Products
Base Pairing
Sample Size
Single Nucleotide Polymorphism
Genome
Genes

Keywords

  • Alcohol
  • Behavioral genetics
  • GWAS
  • Heritability
  • Nicotine
  • Tobacco

Cite this

@article{3e2fc6ffebee4523aeb0eb8dcb8b2ad2,
title = "Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use",
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",
author = "Brazel, {David M.} and Yu Jiang and Hughey, {Jordan M.} and Val{\'e}rie Turcot and Xiaowei Zhan and Jian Gong and Chiara Batini and Weissenkampen, {J. Dylan} and Liu, {Meng Zhen} and Praveen Surendran and Robin Young and Barnes, {Daniel R.} and Nielsen, {Sune Fallgaard} and Asif Rasheed and Maria Samuel and Wei Zhao and Jukka Kontto and Markus Perola and Muriel Caslake and {de Craen}, {Anton J.M.} and Stella Trompet and Maria Uria-Nickelsen and Anders Malarstig and Reily, {Dermot F.} and Maarten Hoek and Thomas Vogt and Jukema, {J. Wouter} and Naveed Sattar and Ian Ford and Packard, {Chris J.} and Alam, {Dewan S.} and Majumder, {Abdulla al Shafi} and {Di Angelantonio}, Emanuele and Rajiv Chowdhury and Philippe Amouyel and Dominique Arveiler and Stefan Blankenberg and Jean Ferri{\`e}res and Frank Kee and Kari Kuulasmaa and Martina M{\"u}ller-Nurasyid and Giovanni Veronesi and Jarmo Virtamo and {EPIC-CVD Consortium}, Consortium and Philippe Frossard and Nordestgaard, {B{\o}rge Gr{\o}nne} and Danish Saleheen and John Danesh and Butterworth, {Adam S.} and Howson, {Joanna M.M.} and Erzurumluoglu, {A. Mesut} and Jackson, {Victoria E.} and Melbourne, {Carl A.} and Varga, {Tibor V.} and Warren, {Helen R.} and Vinicius Tragante and Ioanna Tachmazidou and Harris, {Sarah E.} and Evangelos Evangelou and Jonathan Marten and Weihua Zhang and Elisabeth Altmaier and Jian'an Luan and Claudia Langenberg and Scott, {Robert A.} and Hanieh Yaghootkar and Kathleen Stirrups and Stavroula Kanoni and Eirini Marouli and Fredrik Karpe and Dominiczak, {Anna F.} and Peter Sever and Neil Poulter and Olov Rolandsson and Clemens Baumbach and Saima Afaq and Chambers, {John C.} and Kooner, {Jaspal S.} and Wareham, {Nicholas J.} and Frida Renstr{\"o}m and G{\"o}ran Hallmans and Marioni, {Riccardo E.} and Janie Corley and Starr, {John M.} and Niek Verweij and {de Boer}, {Rudolf A.} and {van der Meer}, Peter and Ersin Yavas and Ilonca Vaartjes and Bots, {Michiel L.} and Asselbergs, {Folkert W.} and Grabe, {Hans J.} and Henry V{\"o}lzke and Matthias Nauck and Stefan Weiss and Pharoah, {Paul D.P.} and Dunning, {Alison M.} and Dennis, {Joe G.} and Thompson, {Deborah J.} and Kyriaki Michailidou and Easton, {Douglas F.} and Antoniou, {Antonis C.} and Jessica Tyrrell and Evelin Mihailov and Samani, {Nilesh J.} and Kaixin Zhou and Neville, {Matthew J.} and Andres Metspalu and Palmer, {Colin N.A.} and Hall, {Ian P.} and Strachan, {David P.} and Deary, {Ian J.} and Frayling, {Tim M.} and Caroline Hayward and {van der Harst}, Pim and Eleftheria Zeggini and {Understanding Society Scientific Group}, {Society Scientific Group} and Munroe, {Patricia B.} and Jansson, {Jan H{\aa}kan} and Franks, {Paul W.} and Panos Deloukas and Caulfield, {Mark J.} and Wain, {Louise V.} and Tobin, {Martin D.} and Sarah Bertelsen and Chou, {Yi Ling} and Faul, {Jessica D.} and Jeff Haessler and Hammerschlag, {Anke R.} and Chris Hsu and Manav Kapoor and Dongbing Lai and Nhung Le and {de Leeuw}, {Christiaan A.} and Anu Loukola and Massimo Mangino and Giorgio Pistis and Beenish Qaiser and Rebecca Rohde and Yaming Shao and Heather Stringham and Leah Wetherill and Arpana Agrawal and Laura Bierut and Chu Chen and Eaton, {Charles B.} and Alison Goate and Christopher Haiman and Andrew Heath and Iacono, {William G.} and Martin, {Nicholas G.} and Polderman, {Tinca J.} and Alex Reiner and John Rice and David Schlessinger and Scholte, {H. Steven} and Smith, {Jennifer A.} and Tardif, {Jean Claude} and Tindle, {Hilary A.} and {van der Leij}, {Andries R.} and Michael Boehnke and Jenny Chang-Claude and Francesco Cucca and David, {Sean P.} and Tatiana Foroud and Kardia, {Sharon L.R.} and Charles Kooperberg and Markku Laakso and Guillaume Lettre and Pamela Madden and Matt McGue and Kari North and Danielle Posthuma and Timothy Spector and Daniel Stram and Weir, {David R.} and Jaakko Kaprio and Abecasis, {Gon{\cc}alo R.} and Liu, {Dajiang J.} and Scott Vrieze and {CHD Exome+ Consortium} and {Consortium for Genetics of Smoking Behaviour}",
note = "Copyright {\circledC} 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "12",
day = "6",
doi = "10.1016/j.biopsych.2018.11.024",
language = "English",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",

}

Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use. / CHD Exome+ Consortium; Consortium for Genetics of Smoking Behaviour.

In: Biological Psychiatry, 06.12.2018.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

AU - Brazel, David M.

AU - Jiang, Yu

AU - Hughey, Jordan M.

AU - Turcot, Valérie

AU - Zhan, Xiaowei

AU - Gong, Jian

AU - Batini, Chiara

AU - Weissenkampen, J. Dylan

AU - Liu, Meng Zhen

AU - Surendran, Praveen

AU - Young, Robin

AU - Barnes, Daniel R.

AU - Nielsen, Sune Fallgaard

AU - Rasheed, Asif

AU - Samuel, Maria

AU - Zhao, Wei

AU - Kontto, Jukka

AU - Perola, Markus

AU - Caslake, Muriel

AU - de Craen, Anton J.M.

AU - Trompet, Stella

AU - Uria-Nickelsen, Maria

AU - Malarstig, Anders

AU - Reily, Dermot F.

AU - Hoek, Maarten

AU - Vogt, Thomas

AU - Jukema, J. Wouter

AU - Sattar, Naveed

AU - Ford, Ian

AU - Packard, Chris J.

AU - Alam, Dewan S.

AU - Majumder, Abdulla al Shafi

AU - Di Angelantonio, Emanuele

AU - Chowdhury, Rajiv

AU - Amouyel, Philippe

AU - Arveiler, Dominique

AU - Blankenberg, Stefan

AU - Ferrières, Jean

AU - Kee, Frank

AU - Kuulasmaa, Kari

AU - Müller-Nurasyid, Martina

AU - Veronesi, Giovanni

AU - Virtamo, Jarmo

AU - EPIC-CVD Consortium, Consortium

AU - Frossard, Philippe

AU - Nordestgaard, Børge Grønne

AU - Saleheen, Danish

AU - Danesh, John

AU - Butterworth, Adam S.

AU - Howson, Joanna M.M.

AU - Erzurumluoglu, A. Mesut

AU - Jackson, Victoria E.

AU - Melbourne, Carl A.

AU - Varga, Tibor V.

AU - Warren, Helen R.

AU - Tragante, Vinicius

AU - Tachmazidou, Ioanna

AU - Harris, Sarah E.

AU - Evangelou, Evangelos

AU - Marten, Jonathan

AU - Zhang, Weihua

AU - Altmaier, Elisabeth

AU - Luan, Jian'an

AU - Langenberg, Claudia

AU - Scott, Robert A.

AU - Yaghootkar, Hanieh

AU - Stirrups, Kathleen

AU - Kanoni, Stavroula

AU - Marouli, Eirini

AU - Karpe, Fredrik

AU - Dominiczak, Anna F.

AU - Sever, Peter

AU - Poulter, Neil

AU - Rolandsson, Olov

AU - Baumbach, Clemens

AU - Afaq, Saima

AU - Chambers, John C.

AU - Kooner, Jaspal S.

AU - Wareham, Nicholas J.

AU - Renström, Frida

AU - Hallmans, Göran

AU - Marioni, Riccardo E.

AU - Corley, Janie

AU - Starr, John M.

AU - Verweij, Niek

AU - de Boer, Rudolf A.

AU - van der Meer, Peter

AU - Yavas, Ersin

AU - Vaartjes, Ilonca

AU - Bots, Michiel L.

AU - Asselbergs, Folkert W.

AU - Grabe, Hans J.

AU - Völzke, Henry

AU - Nauck, Matthias

AU - Weiss, Stefan

AU - Pharoah, Paul D.P.

AU - Dunning, Alison M.

AU - Dennis, Joe G.

AU - Thompson, Deborah J.

AU - Michailidou, Kyriaki

AU - Easton, Douglas F.

AU - Antoniou, Antonis C.

AU - Tyrrell, Jessica

AU - Mihailov, Evelin

AU - Samani, Nilesh J.

AU - Zhou, Kaixin

AU - Neville, Matthew J.

AU - Metspalu, Andres

AU - Palmer, Colin N.A.

AU - Hall, Ian P.

AU - Strachan, David P.

AU - Deary, Ian J.

AU - Frayling, Tim M.

AU - Hayward, Caroline

AU - van der Harst, Pim

AU - Zeggini, Eleftheria

AU - Understanding Society Scientific Group, Society Scientific Group

AU - Munroe, Patricia B.

AU - Jansson, Jan Håkan

AU - Franks, Paul W.

AU - Deloukas, Panos

AU - Caulfield, Mark J.

AU - Wain, Louise V.

AU - Tobin, Martin D.

AU - Bertelsen, Sarah

AU - Chou, Yi Ling

AU - Faul, Jessica D.

AU - Haessler, Jeff

AU - Hammerschlag, Anke R.

AU - Hsu, Chris

AU - Kapoor, Manav

AU - Lai, Dongbing

AU - Le, Nhung

AU - de Leeuw, Christiaan A.

AU - Loukola, Anu

AU - Mangino, Massimo

AU - Pistis, Giorgio

AU - Qaiser, Beenish

AU - Rohde, Rebecca

AU - Shao, Yaming

AU - Stringham, Heather

AU - Wetherill, Leah

AU - Agrawal, Arpana

AU - Bierut, Laura

AU - Chen, Chu

AU - Eaton, Charles B.

AU - Goate, Alison

AU - Haiman, Christopher

AU - Heath, Andrew

AU - Iacono, William G.

AU - Martin, Nicholas G.

AU - Polderman, Tinca J.

AU - Reiner, Alex

AU - Rice, John

AU - Schlessinger, David

AU - Scholte, H. Steven

AU - Smith, Jennifer A.

AU - Tardif, Jean Claude

AU - Tindle, Hilary A.

AU - van der Leij, Andries R.

AU - Boehnke, Michael

AU - Chang-Claude, Jenny

AU - Cucca, Francesco

AU - David, Sean P.

AU - Foroud, Tatiana

AU - Kardia, Sharon L.R.

AU - Kooperberg, Charles

AU - Laakso, Markku

AU - Lettre, Guillaume

AU - Madden, Pamela

AU - McGue, Matt

AU - North, Kari

AU - Posthuma, Danielle

AU - Spector, Timothy

AU - Stram, Daniel

AU - Weir, David R.

AU - Kaprio, Jaakko

AU - Abecasis, Gonçalo R.

AU - Liu, Dajiang J.

AU - Vrieze, Scott

AU - CHD Exome+ Consortium

AU - Consortium for Genetics of Smoking Behaviour

N1 - Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PY - 2018/12/6

Y1 - 2018/12/6

N2 - 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.

AB - 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.

KW - Alcohol

KW - Behavioral genetics

KW - GWAS

KW - Heritability

KW - Nicotine

KW - Tobacco

UR - http://www.scopus.com/inward/record.url?scp=85060224532&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060224532&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2018.11.024

DO - 10.1016/j.biopsych.2018.11.024

M3 - Article

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

ER -