Elsevier

Biological Psychiatry

Volume 85, Issue 11, 1 June 2019, Pages 946-955
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2018.11.024Get rights and content

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.

Section snippets

Methods and Materials

Seventeen studies contributed summary statistics for meta-analysis. These studies, their sample sizes, and available phenotypes are listed in Tables S1 and S2 in Supplement 1. We augmented our 16 exome chip cohorts with the UK Biobank, in which imputation to the Haplotype Reference Consortium panel was used in lieu of an exome chip array. All individuals were of European ancestry, as determined by genetic principal components.

Results

GWAS analyses behaved well, with genomic control values for the GWAS across exome chip and UK Biobank imputed variants between 1.05 and 1.3. The intercept for LD score regression ranged between 0.99 and 1.1, indicating absent or minimal effects of population stratification (per-study genomic control values can be found in Table S2 in Supplement 1). A total of 171 loci were identified under the genome-wide significance threshold (p < 5 × 10–8), including 3, 11, 17, 93, and 47 loci for age of

Discussion

With a maximum sample size ranging from 152,348 to 433,216, the present study is the largest study to date of low-frequency nonsynonymous and loss-of-function variants in smoking and alcohol use. Our meta-analytic study design combined studies genotyped on the exome array with imputed genotypes in the UK Biobank and allowed us to comprehensively evaluate the contribution of rare and low-frequency variants to the etiology of tobacco and alcohol use. All told, we identified 171 genome-wide

Acknowledgments and Disclosures

This research has been conducted using the UK Biobank Resource under Application Number 16651. This work was supported by the National Institute on Drug Abuse and the National Human Genome Research Institute of the National Institutes of Health Grant Nos. R01DA037904 (to SIV), R21DA040177 (to DJL), R01HG008983 (to DJL), R01GM126479 (to DJL), and 5T32DA017637-13 (to DMB); funding sources listed in the Supplementary Note; and a National Science Foundation Graduate Research Fellowship (to JMH).

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    CHD Exome+ Consortium: 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 Angelantonio, Rajiv Chowdhury, Philippe Amouyel, Dominique Arveiler, Stefan Blankenberg, Jean Ferrières, Frank Kee, Kari Kuulasmaa, Martina Müller-Nurasyid, Giovanni Veronesi, Jarmo Virtamo, EPIC-CVD Consortium, Philippe Frossard, Børge Grønne Nordestgaard, Danish Saleheen, John Danesh, Adam S. Butterworth, Joanna M.M. Howson.

    Consortium for Genetics of Smoking Behaviour: 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 Renström, Göran 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 Völzke, 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, Understanding Society Scientific Group, Patricia B. Munroe, Jan-Håkan Jansson, Paul W. Franks, Panos Deloukas, Mark J Caulfield, Louise V. Wain, Martin D. Tobin.

    1

    DMB, YJ, and JMH contributed equally to this work.

    2

    This work was jointly supervised by SIV and DJL.

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