Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls

Abstract

Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21-6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10(-16)), 6p21 (P = 2.3 × 10(-14)) and 15q25 (P = 2.2 × 10(-63)). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16(INK4A)/p14(ARF)/CDKN2B/p15(INK4B)/ANRIL; rs1333040, P = 3.0 × 10(-7)) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10(-8)). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.

Figure 1.

Manhattan and quantile–quantile (Q–Q) plots for the meta-analysis of lung cancer overall and major histologies. Combined ORs and P-values were derived from the per-allele model. Core 318 094 SNPs corresponding to the Illumina HumanHap 300 BeadChips array are shown in the Manhattan plots as round-shaped. Additional 217 914 SNPs corresponding to the Illumina HumanHap550 array are shown as triangle-shaped. (A) The Manhattan plot of P-values for the fixed-effects model for the overall meta-analysis. rs1551821 at 18q21.1 reached genome-wide significance for the fixed effect (effect allele C, OR = 0.81, P = 6.01 × 10⁻¹⁰). However, strong heterogeneity by study (P_het = 3.11 × 10⁻⁶, I² = 85%) driven by two UK studies (OR = 0.90, P = 0.06 when the ICR removed), observed deviation from the Hardy–Weinberg equilibrium in the SLRI/Toronto, HGF Germany and MDACC studies and no evidence of association for the correlated SNPs within locus indicated possible chance finding (Supplementary Material, Fig. S2). (B) The Q–Q plot for P-values in the −log₁₀ scale for the fixed-effects model for the core 318 094 SNPs. The inflation factor for the 90% bottom SNPs (λ) = 1.10. The red line represents the concordance of observed and expected values. The shaded area indicates a 99% concentration band. (C) The Manhattan plot of P-values for the fixed-effects model for adenocarcinoma histology. The inflation factor for the 90% bottom SNPs (λ) = 1.05. (D) The Manhattan plot of P-values for the fixed-effects model for squamous cell carcinoma histology. The inflation factor for the 90% bottom SNPs (λ) = 1.04.

Figure 2.

Association between SNPs on 5p15.33, 6p22.3-6p21.31, 9p21.3, 12p13.33 and 15q25.1 and the risk of lung cancer. Combined ORs and 95% CIs were derived from the per-allele model. Except for the ORs for the random-effects model, results for the fixed-effects model are presented. Squares represent ORs; size of the square represents the inverse of the variance of the log ORs; horizontal lines represent 95% CIs; diamonds represent the summary estimate combining the study-specific estimates with a fixed-effects model; solid vertical lines represent OR = 1; dashed vertical lines represent the overall ORs. Results within different strata (histology, age, smoking, gender, family history and stage) are presented for the fixed-effects model. The allele frequency of selected SNPs by study and the case–control status are presented in Supplementary Material, Table S7. ¹Heterogeneity assessed between ever and never smoking groups. NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer; LCLC, large-cell lung cancer.

Figure 2.

Association between SNPs on 5p15.33, 6p22.3-6p21.31, 9p21.3, 12p13.33 and 15q25.1 and the risk of lung cancer. Combined ORs and 95% CIs were derived from the per-allele model. Except for the ORs for the random-effects model, results for the fixed-effects model are presented. Squares represent ORs; size of the square represents the inverse of the variance of the log ORs; horizontal lines represent 95% CIs; diamonds represent the summary estimate combining the study-specific estimates with a fixed-effects model; solid vertical lines represent OR = 1; dashed vertical lines represent the overall ORs. Results within different strata (histology, age, smoking, gender, family history and stage) are presented for the fixed-effects model. The allele frequency of selected SNPs by study and the case–control status are presented in Supplementary Material, Table S7. ¹Heterogeneity assessed between ever and never smoking groups. NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer; LCLC, large-cell lung cancer.

Figure 3.

The regional plot of the 15q25, 5p15 and 6p21–6p22 loci after controlling for most significantly associated SNPs within the locus. P-values for log-additive association results (−log₁₀) are shown with the recombination rate based on HapMap phase II data. (A) 15q25 locus. Black dots, results (−log₁₀ P) for SNPs genotyped within the region. Blue, results after the inclusion of rs6495309 allele dosage as a covariate; green, results after the inclusion of rs1051730 allele dosage as a covariate; red, a model includes allele dosages for both SNPs. rs7173743 showed association (P = 1.4 × 10⁻⁵) after controlling for both SNPs with high heterogeneity between studies I² = 99.1%. (B) 5p15 locus. Black dots, results (−log₁₀ P) for SNPs genotyped within the region. Blue, results after the inclusion of rs2736100 allele dosage as a covariate, TERT; green, allele dosage for rs401681 is included as a covariate, CLPTM1L; red, allele dosages for both SNPs are included as a covariate. (C) 6p21–6p22 locus. Black dots, (−log₁₀ P) for SNPs genotyped within the region; green, allele dosage for rs3117582 is included as a covariate, BAG6/BAT3. Two SNPs (rs1003581 and rs130065) reaching genome–wide significance after conditioning on rs3117582 were observed within the same locus with strong heterogeneity by study (I² = 99%) suggesting false findings.