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Meta-Analysis
. 2010 May;42(5):436-40.
doi: 10.1038/ng.572. Epub 2010 Apr 25.

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

Jason Z Liu  1 , Federica Tozzi, Dawn M Waterworth, Sreekumar G Pillai, Pierandrea Muglia, Lefkos Middleton, Wade Berrettini, Christopher W Knouff, Xin Yuan, Gérard Waeber, Peter Vollenweider, Martin Preisig, Nicholas J Wareham, Jing Hua Zhao, Ruth J F Loos, Inês Barroso, Kay-Tee Khaw, Scott Grundy, Philip Barter, Robert Mahley, Antero 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, Joseph M Lindsay, Ron Waksman, Stephen Epstein, James F Wilson, Sarah H Wild, Harry Campbell, Veronique Vitart, Muredach P Reilly, Mingyao Li, Liming Qu, Robert Wilensky, William Matthai, Hakon H Hakonarson, Daniel J Rader, Andre Franke, Michael Wittig, Arne Schäfer, Manuela Uda, Antonio Terracciano, Xiangjun Xiao, Fabio Busonero, Paul Scheet, David Schlessinger, David St Clair, Dan Rujescu, Gonçalo R Abecasis, Hans Jörgen Grabe, Alexander Teumer, Henry Völzke, Astrid Petersmann, Ulrich John, Igor Rudan, Caroline Hayward, Alan F Wright, Ivana Kolcic, Benjamin J Wright, John R Thompson, Anthony J Balmforth, Alistair S Hall, Nilesh J Samani, Carl A Anderson, Tariq Ahmad, Christopher G Mathew, Miles Parkes, Jack Satsangi, Mark Caulfield, Patricia B Munroe, Martin Farrall, Anna Dominiczak, Jane Worthington, Wendy Thomson, Steve Eyre, Anne Barton; Wellcome Trust Case Control Consortium; Vincent Mooser, Clyde Francks, Jonathan Marchini
Affiliations
Meta-Analysis

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

Jason Z Liu et al. Nat Genet. 2010 May.

Abstract

Smoking is a leading global cause of disease and mortality. 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.

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Figures

Figure 1
Figure 1
Manhattan plot showing the significance of association of all SNPs in genome-wide SQ meta-analysis. SNPs are plotted on the x-axis according to their positions on each chromosome, against association with SQ on the y-axis (−log10 P-value). SNPs with p-values less than 1.0E-05 are highlighted in green.
Figure 2
Figure 2
Chromosome 15q25 signal plots. Top: Signal plot based on 1000 Genomes imputation and meta-analysis of SQ association. SNPs are plotted by their positions on the chromosome, against association with SQ (−log10 p-value) on the left Y-axis. The five SNPs with the lowest p-values from the HapMap imputation are highlighted in red. The five SNPs with the lowest p-values from the 1000 Genomes imputation are highlighted in green (unless already coloured red). The rs identities of highlighted SNPs are given in the box. Recombination rates across the region are shown by the red line plotted against the right y-axis. Middle: Chromosome 15q25 signal plot based on 1000 Genomes imputation and meta-analysis of SQ association, conditional on the SNP rs55853698. The five SNPs with the lowest p-values from the conditional analysis are highlighted in green. The five SNPs with the lowest p-values from the unconditioned HapMap-imputation analysis are highlighted in red. Bottom: Genes and the positions of exons (using data from the UCSC genome browser; URL is given below).
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