Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use
David M Brazel, Yu Jiang, Jordan M Hughey, Valerie Turcot, Xiaowei Zhan, Jian Gong, Chiara Batini, J Dylan Weissenkampen, MengZhen Liu, Daniel R Barnes, Sarah Bertelsen, Yi-Ling Chou, A Mesut Erzurumluoglu, Jessica D Faul, Jeff Haessler, Anke R Hammerschlag, Chris Hsu, Manav Kapoor, Dongbing Lai, Nhung Le Show all
Biological Psychiatry | ELSEVIER SCIENCE INC | Published : 2019
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, ..View full abstract
Awarded by National Human Genome Research Institute of the National Institutes of Health
Awarded by National Science Foundation Graduate Research Fellowship Program
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 (toDJL), R01HG008983 (to DJL), R01GM126479 (to DJL), and 5T32DA01763713 (to DMB); funding sources listed in the Supplementary Note; and a National Science Foundation Graduate Research Fellowship (to JMH).This material is based on work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE1255832 (to JMH). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.The members of the Consortium for Genetics of Smoking Behaviour report the following: Paul W. Franks has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Neil Poulter has received financial support from several pharmaceutical companies that manufacture either blood pressure lowering or lipid lowering agents or both and consultancy fees. Peter Sever has received research awards from Pfizer. Mark J. Caulfield is Chief Scientist for Genomics England, a UK government company.