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 × 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.Lung cancer is frequently cited as a malignancy attributable solely to environmental exposures -primarily cigarette smoke. However, evidence that genetic factors influence lung cancer © 2008 Nature Publishing Group Correspondence should be addressed to C.I.A. (E-mail: camos@mdanderson.org). 6 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS Texas: C.I.A. and M.R.S. conceived of this study. M.R.S. established the Texas lung cancer study. C.I.A. supervised and performed the analyses. G.M. provided oversight in manuscript development and in the conduct of genetic studies. I.P.G., Q.D., Q.Z., W.V.C. and X.G. performed statistical analyses. S.S. developed and implemented statistical procedures for joint analysis. X.W. and J. Direct evidence for a genetic predisposition to lung cancer is provided by the increased risk associated with constitutional TP53 (tumor protein p53) 4 and RB1 (retinoblastoma) 5,6 gene mutations, rare mendelian cancer syndromes such as Bloom's 7 and Werner's syndromes 8 , and strongly familial lung cancer 9 . The genetic basis of inherited susceptibility to lung cancer outside the context of these disorders is at present undefined, but a model in which high-risk alleles account for all of the excess familial risk seems unlikely. Alternatively, part of the inherited genetic risk may be caused by low-penetrance alleles. This hypothesis implies that testing for allelic association should be a powerful strategy for identifying alleles that predispose to lung cancer.We conducted a genome-wide association study (GWAS) of histologically confirmed nonsmall cell lung cancer (NSCLC) to identify common low-penetrance alleles influencing lung cancer risk. To minimize confounding effects from cigarette smoking and increase the power to detect genetic effects, we frequency matched controls to cases according to smoking behavior. We also matched controls to cases by age (within 5 year categories) and sex, and we further matched former smokers by year...

Gene variance in the nicotinic receptor cluster (CHRNA5‐CHRNA3‐CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers

“…We also confirmed the associations between this variance and incident COPD 4, 13, 14, tobacco‐related cancers 7, 15, 16, lung cancer 4, 7, 15, 17, 18, 19, 20, 21 and smoking quantity 2, 3, 7, indicating an exciting overlap of genetic influence on ND and smoking‐related diseases. As mentioned above, this region of the nAChRs is characterized by high correlation and the results should be interpreted as an association with the cluster instead of the rs1051730.…”

Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: Converging evidence from human and animal research

“…These SNPs, along with those identified by Saccone and colleagues [142], belong to a common CHRNA5-CHRNA3 haplotype that is associated with risk for smoking quantity. Three independent genome-wide association studies have also linked the CHRNA5-CHRNA3-CHRNB4 gene cluster to risk for lung cancer, smoking quantity, and nicotine dependence [1,74,171]. A SNP in CHRNA3 (rs1051730) that is in linkage disequilibrium with other SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster [142] was associated with smoking quantity, nicotine dependence, risk for peripheral arterial disease [171], and risk for lung cancer [1,74,171].…”

“…Three independent genome-wide association studies have also linked the CHRNA5-CHRNA3-CHRNB4 gene cluster to risk for lung cancer, smoking quantity, and nicotine dependence [1,74,171]. A SNP in CHRNA3 (rs1051730) that is in linkage disequilibrium with other SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster [142] was associated with smoking quantity, nicotine dependence, risk for peripheral arterial disease [171], and risk for lung cancer [1,74,171]. Furthermore, Hung and colleagues [74] identified a non-synonymous SNP in CHRNA5 (rs16969968) that was associated with risk for lung cancer, and this finding was replicated in five independent studies.…”

“…Although these data suggest that the CHRNA5-CHRNA3-CHRNB4 gene cluster is directly associated with risk for lung cancer, it is possible that this gene cluster alters risk for nicotine dependence, and subsequent tobacco smoking increases risk for lung cancer. Some evidence suggests that the link between the CHRNA5-CHRNA3-CHRNB4 gene cluster and lung cancer is independent from any association between the gene cluster and nicotine dependence [1,74], whereas other research indicates that risk for lung cancer may be indirectly modulated by an association between the CHRNA5-CHRNA3-CHRNB4 gene cluster and nicotine dependence [171]. Together, these data suggest that polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster may influence several smoking phenotypes and alter risk for lung cancer, but it is unclear whether these effects are mediated by SNPs in one or more of the genes in this cluster.…”

The pursuit of genome-wide association studies: where are we now?

“…[85][86][87] For lung cancer, the first convincing genetic locus also emerged, 15q25, which contained several genes encoding for nicotinic acetylcholine receptors. [88][89][90] The combination of three GWAS further identified additional susceptibility loci for this common cancer, 75 where one of the loci (5p15.33) was also identified by another GWAS. 91 The 5p15.33 locus contains two genes, TERT and CLPTM1L, and interestingly the sequence variants at this locus were found to be associated with several cancers.…”