Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study

Abstract

To explore the impact of common variation on the risk of developing lung cancer, we conducted a two-phase genome-wide association (GWA) study. In phase 1, we compared the genotypes of 511,919 tagging single nucleotide polymorphisms (SNP) in 1,952 cases and 1,438 controls; in phase 2, 30,568 SNPs were genotyped in 2,465 cases and 3,005 controls. SNP selection was based on best supported P values from phase 1 and two other GWA studies of lung cancer. In the combined analysis of phases 1 and 2, the strongest associations identified were defined by SNPs mapping to 15q25.1 (rs12914385; P = 3.19 x 10(-16)), 5p15.33 (rs4975616; P = 6.66 x 10(-7)), and 6p21.33 (rs3117582; P = 9.13 x 10(-7)). Variation at 15q25.1, but not 5p15.33 or 6p21.33, was strongly associated with smoking behavior with risk alleles correlated to higher consumption. Variation at 5p15.33 was shown to significantly influence induction of lung cancer histology. Pooling data from the four series provided 21,620 genotypes for 7,560 cases and 8,205 controls. A meta-analysis provided increased support that variation at 15q25.1 (rs8034191; P = 3.24 x 10(-26)), 5p15.33 (rs4975616; P = 2.99 x 10(-9)), and 6p21.33 (rs3117582; P = 4.46 x 10(-10)) influences lung cancer risk. The next best-supported associations were attained at 15q15.2 (rs748404: P = 1.08 x 10(-6)) and 10q23.31 (rs1926203; P = 1.28 x 10(-6)). These data indicate few common variants account for 1% of the excess familial risk underscoring the necessity of having additional large sample series for gene discovery.

Figure 1. UK-GWA study data quality control of (a) Phase 1, (b) Phase 2

Figure 2. Regioal plots of the (a) 15q25.1 (b) 5p15.33 and (c) 6p21.33 associations

Each panel shows single-marker association statistics (as −log₁₀P) from the analysis of UK-GWA study Phase 1 (diamonds), UK-GWA study Phase 2 (squares), Phases 1 and 2 combined (triangles), as a function of genomic position (NCBI build 36.1). The recombination rate across each region in HapMap CEU is shown in black (right y axis). Also shown for 15q25.1 (a) and 5p15.33 (b) is the relative position of genes mapping to each region of association, there are a large number of genes mapping to the 6p21.33 (c) region so for clarity only BAT3 and TNXB are illustrated. Exons of genes have been redrawn to show the relative positions in the gene, therefore maps are not to physical scale. LD plot was generated using UK-GWA study Phase 2 controls; values and shading show r² between each pair of SNPs; the darker the shading, the greater extent of LD.

Figure 3. Power to detect lung cancer susceptibility alleles in UK-GWA study (Phases 1 and 2 combined) and the UK-IARC-Texas GWA studies meta-analysis

The dashed and solid lines show the power of the UK-GWA study (Phases 1 and 2 combined) and the UK (Phases 1 and 2)-IARC-Texas-GWA studies meta-analysis to identify susceptibility alleles with different minor allele frequencies respectively. Power to identify 5p15.33 (rs4975616), 6p21.33 (rs3117582), and 15q25.1 (rs12914385), variants in each analysis denoted by squares and diamonds respectively (P= 10⁻⁷).