A variant associated with nicotine dependence, lung cancer and peripheral arterial disease

Abstract

Smoking is a leading cause of preventable death, causing approximately five million premature deaths world-wide each year 1, 2 . Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) 3-8 has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important for public health reasons 9, 10 . Smoking is the major risk factor for lung cancer (LC) [11][12][13][14] , and one of the main risk factors for peripheral arterial disease (PAD) [15][16][17] . We have identified a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in 15,771 smokers (P=6×10 −20 ). The same variant associated with ND in a previous genome-wide association study using low quantity smokers as controls (OR=1.3, P=1×10 −3 ) 18,19 , and with a similar approach we observe a highly significant association with ND (OR =1.40, P=7×10 −15 ). Comparison of LC (N=1,024) and PAD (N= 2,738) cases with about 30,000 population controls each showed that the variant confers risk of LC (OR=1.31, P=1.5×10 −8 ) and PAD (OR=1.19, P=1.4×10 −7 ). The findings highlight the role of nicotine addiction in the pathogenesis of other serious diseases and provide a case study of the role of active gene-environment correlation 20 in the pathogenesis of disease.To perform a genome-wide association (GWA) study of smoking quantity (SQ), we utilised questionnaire data limited to basic questions on smoking behaviour that were available for a large number of lifetime smokers. The GWA scan comprises 10,995 Icelandic smokers who Reprints and permissions information is available at www.nature.com/reprints.

Polygenic risk scores for schizophrenia and bipolar disorder associate with addiction

“…FTND data were obtained from questionnaires answered by participants in deCODE's study of nicotine dependence (ND) (2004–2014)(Thorgeirsson et al 2008). Responses to FTND questions generate a score of 0–10, with higher scores representing greater ND (Heatherton et al 1991).…”

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.…”