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