Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1

Abstract

To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 x 10(-17)) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.

Figure 1

Results from genome-wide association analysis of directly tested SNPs in the Texas discovery set using Illumina 300K HumanHap v1.1 Beadchips.

Figure 2

The 15q25.1 locus. The top panel shows SNP single marker association results. Results in blue depict genotyped SNPs, and results in red are for imputed SNPs. All known genes and predicted transcripts in the local area are shown. Positions are that of University of California Santa Cruz Genome Browser March 2006 assembly; NCBI Build 36.1. The bottom panel shows the LD structure at 15q21.4. Boxes are shaded according to the standardized disequilibrium coefficient, D, derived from Phase 1 genotypes in Haploview (v3.2).

Figure 3

Effects of SNPs according to smoking behavior in current, former and never smokers adjusting for age, sex and packyears of tobacco smoke exposure. (a–c) The x axis indicates the extent of exposure, starting with never smokers (UK population, panel c only), followed by former smokers who quit 24 or more years ago, former smokers who quit 15–23 years ago, former smokers who quit less than 15 years ago and current smokers. Panel a presents data from the Texas discovery set, panel b presents data from the Texas replication set and panel c presents data from the UK replication set.