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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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@article{e25f4518c80d4bf3bfff9b2f8be81e58,
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.",
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 MengZhen Liu and Barnes, {Daniel R} and Sarah Bertelsen and Yi-Ling Chou and Erzurumluoglu, {A Mesut} 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 Melbourne, {Carl A} and Giorgio Pistis and Beenish Qaiser and Rebecca Rohde and Yaming Shao and Heather Stringham and Leah Wetherill and Wei Zhao 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 Jean-Claude Tardif and Tindle, {Hilary A} and {van der Leij}, {Andries R} and Michael Boehnke and Nordestgaard, {B{\o}rge G.} and Nielsen, {Sune Fallgaard} and {CHD Exome+ Consortium}",
note = "Copyright {\circledC} 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = "6",
doi = "10.1016/j.biopsych.2018.11.024",
language = "English",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier Inc",

}

RIS

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, MengZhen

AU - Barnes, Daniel R

AU - Bertelsen, Sarah

AU - Chou, Yi-Ling

AU - Erzurumluoglu, A Mesut

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 - Melbourne, Carl A

AU - Pistis, Giorgio

AU - Qaiser, Beenish

AU - Rohde, Rebecca

AU - Shao, Yaming

AU - Stringham, Heather

AU - Wetherill, Leah

AU - Zhao, Wei

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 - CHD Exome+ Consortium

A2 - Nordestgaard, Børge G.

A2 - Nielsen, Sune Fallgaard

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

PY - 2019/6

Y1 - 2019/6

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.

U2 - 10.1016/j.biopsych.2018.11.024

DO - 10.1016/j.biopsych.2018.11.024

M3 - Journal article

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

ER -

ID: 56634857