Meta-analysis and imputation refines the association of 15q25 with smoking quantity.
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- Authors
- Liu, Jason Z; Tozzi, Federica; Waterworth, Dawn M; Pillai, Sreekumar G; Muglia, Pierandrea; Middleton, Lefkos; Berrettini, Wade; Knouff, Christopher W; Yuan, Xin; Waeber, GΓ©rard; Vollenweider, Peter; Preisig, Martin; Wareham, Nicholas J; Zhao, Jing Hua; Loos, Ruth J F; Barroso, InΓͺs; Khaw, Kay-Tee; Grundy, Scott; Barter, Philip; Mahley, Robert; Kesaniemi, Antero; McPherson, Ruth; Vincent, John B; Strauss, John; Kennedy, James L; Farmer, Anne; McGuffin, Peter; Day, Richard; Matthews, Keith; Bakke, Per; Gulsvik, Amund; Lucae, Susanne; Ising, Marcus; Brueckl, Tanja; Horstmann, Sonja; Wichmann, H-Erich; Rawal, Rajesh; Dahmen, Norbert; Lamina, Claudia; Polasek, Ozren; Zgaga, Lina; Huffman, Jennifer; Campbell, Susan; Kooner, Jaspal; Chambers, John C; Burnett, Mary Susan; Devaney, Joseph M; Pichard, Augusto D; Kent, Kenneth M; Satler, Lowell; Lindsay, Joseph M; Waksman, Ron; Epstein, Stephen; Wilson, James F; Wild, Sarah H; Campbell, Harry; Vitart, Veronique; Reilly, Muredach P; Li, Mingyao; Qu, Liming; Wilensky, Robert; Matthai, William; Hakonarson, Hakon H; Rader, Daniel J; Franke, Andre; Wittig, Michael; SchΓ€fer, Arne; Uda, Manuela; Terracciano, Antonio; Xiao, Xiangjun; Busonero, Fabio; Scheet, Paul; Schlessinger, David; St Clair, David; Rujescu, Dan; Abecasis, GonΓ§alo R; Grabe, Hans JΓΆrgen; Teumer, Alexander; VΓΆlzke, Henry; Petersmann, Astrid; John, Ulrich; Rudan, Igor; Hayward, Caroline; Wright, Alan F; Kolcic, Ivana; Wright, Benjamin J; Thompson, John R; Balmforth, Anthony J; Hall, Alistair S; Samani, Nilesh J; Anderson, Carl A; Ahmad, Tariq; Mathew, Christopher G; Parkes, Miles; Satsangi, Jack; Caulfield, Mark; Munroe, Patricia B; Farrall, Martin; Dominiczak, Anna; Worthington, Jane; Thomson, Wendy; Eyre, Steve; Barton, Anne; Wellcome Trust Case Control Consortium; Mooser, Vincent; Francks, Clyde; Marchini, Jonathan
- Year
- 2010
- Journal
- Nature genetics
- PMID
- 20418889
- DOI
- 10.1038/ng.572
- PMCID
- PMC3612983
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.
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 (βlog10 P-value). SNPs with p-values less than 1.0E-05 are highlighted in green.
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 (βlog10 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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