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

Liu JZ, Tozzi F, Waterworth DM, Pillai SG, Muglia P, Middleton L, Berrettini W, Knouff CW, Yuan X, Waeber G, Vollenweider P, Preisig M, Wareham NJ, Zhao JH, Loos RJ, Barroso I, Khaw KT, Grundy S, Barter P, Mahley R, Kesaniemi A, McPherson R, Vincent JB, Strauss J, Kennedy JL, Farmer A, McGuffin P, Day R, Matthews K, Bakke P, Gulsvik A, Lucae S, Ising M, Brueckl T, Horstmann S, Wichmann HE, Rawal R, Dahmen N, Lamina C, Polasek O, Zgaga L, Huffman J, Campbell S, Kooner J, Chambers JC, Burnett MS, Devaney JM, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Epstein S, Wilson JF, Wild SH, Campbell H, Vitart V, Reilly MP, Li M, Qu L, Wilensky R, Matthai W, Hakonarson HH, Rader DJ, Franke A, Wittig M, Schafer A, Uda M, Terracciano A, Xiao X, Busonero F, Scheet P, Schlessinger D, St Clair D, Rujescu D, Abecasis GR, Grabe HJ, Teumer A, Volzke H, Petersmann A, John U, Rudan I, Hayward C, Wright AF, Kolcic I, Wright BJ, Thompson JR, Balmforth AJ, Hall AS, Samani NJ, Anderson CA, Ahmad T, Mathew CG, Parkes M, Satsangi J, Caulfield M, Munroe PB, Farrall M, Dominiczak A, Worthington J, Thomson W, Eyre S, Barton A, Mooser V, Francks C and Marchini J

Nat Genet (2010) 42:436-40

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.