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 journalArticle

2 Citations (Scopus)

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 (US)
Pages (from-to)946-955
Number of pages10
JournalBiological Psychiatry
Volume85
Issue number11
DOIs
StatePublished - Jun 1 2019
Externally publishedYes

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

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

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, Vol. 85, No. 11, 01.06.2019, p. 946-955.

Research output: Contribution to journalArticle

CHD Exome+ Consortium ; Consortium for Genetics of Smoking Behaviour. / Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use. In: Biological Psychiatry. 2019 ; Vol. 85, No. 11. pp. 946-955.
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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.",
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author = "{CHD Exome+ Consortium} and {Consortium for Genetics of Smoking Behaviour} and 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 Tatiana Foroud",
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T1 - Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

AU - CHD Exome+ Consortium

AU - Consortium for Genetics of Smoking Behaviour

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 - Foroud, Tatiana

PY - 2019/6/1

Y1 - 2019/6/1

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

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U2 - 10.1016/j.biopsych.2018.11.024

DO - 10.1016/j.biopsych.2018.11.024

M3 - Article

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JF - Biological Psychiatry

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