Meta-analysis and imputation refines the association of 15q25 with smoking quantity

Jason Z. Liu, Federica Tozzi, Dawn M. Waterworth, Sreekumar G. Pillai, Pierandrea Muglia, Lefkos Middleton, Wade Berrettini, Christopher W. Knouff, Xin Yuan, Gerard Waeber, Peter Vollenweider, Martin Preisig, Nicholas J. Wareham, Jing Hua Zhao, Ruth J. F. Loos, Ines Barroso, Kay-Tee Khaw, Scott Grundy, Philip Barter, Robert MahleyAntero Kesaniemi, Ruth McPherson, John B. Vincent, John Strauss, James L. Kennedy, Anne Farmer, Peter McGuffin, Richard Day, Keith Matthews, Per Bakke, Amund Gulsvik, Susanne Lucae, Marcus Ising, Tanja Brueckl, Sonja Horstmann, H-Erich Wichmann, Rajesh Rawal, Norbert Dahmen, Claudia Lamina, Ozren Polasek, Lina Zgaga, Jennifer Huffman, Susan Campbell, Jaspal Kooner, John C. Chambers, Mary Susan Burnett, Joseph M. Devaney, Augusto D. Pichard, Kenneth M. Kent, Lowell Satler, Wellcome Trust Case Control Consor

    Research output: Contribution to journalArticle

    453 Citations (Scopus)

    Abstract

    Smoking is a leading global cause of disease and mortality(1). We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

    Original languageEnglish
    Pages (from-to)436-U75
    Number of pages7
    JournalNature Genetics
    Volume42
    Issue number5
    DOIs
    Publication statusPublished - May 2010

    Keywords

    • GENOME-WIDE ASSOCIATION
    • NICOTINE DEPENDENCE
    • LUNG-CANCER
    • SUSCEPTIBILITY LOCUS
    • RISK-FACTORS
    • DISEASE
    • GENES
    • SNPS

    Cite this

    Liu, J. Z., Tozzi, F., Waterworth, D. M., Pillai, S. G., Muglia, P., Middleton, L., Berrettini, W., Knouff, C. W., Yuan, X., Waeber, G., Vollenweider, P., Preisig, M., Wareham, N. J., Zhao, J. H., Loos, R. J. F., Barroso, I., Khaw, K-T., Grundy, S., Barter, P., ... Wellcome Trust Case Control Consor (2010). Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nature Genetics, 42(5), 436-U75. https://doi.org/10.1038/ng.572