Genome-wide meta-analyses identify multiple loci associated with smoking behavior

Abstract

Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], β = 1.03, standard error (s.e.) = 0.053, P = 2.8 × 10−73). Two 10q25 SNPs (rs1329650[G], β = 0.367, s.e. = 0.059, P = 5.7 × 10−10; and rs1028936[A], β = 0.446, s.e. = 0.074, P = 1.3 × 10−9) and one 9q13 SNP in EGLN2 (rs3733829[G], β = 0.333, s.e. = 0.058, P = 1.0 × 10−8) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04–1.08, P = 1.8 × 10−8). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08–1.18, P = 3.6 × 10−8) was significantly associated with smoking cessation.

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.…”

“…Negative health consequences such as cancer, heart disease, stroke and respiratory diseases are well‐known complications, and cigarette smoking is responsible for about 5 million deaths annually (Data from the World Health Organization). Recent genomewide association studies have shown convincing associations between a number of genetic variations and both nicotine dependence (ND) and smoking behaviour 2, 3, 4, 5, 6. The synonymous single nucleotide polymorphism (SNP) rs1051730 on chromosome 15q25, in the gene for the nicotinic acetylcholine receptor (nAChr) subunit CHRNA3, showed the strongest association.…”

“…The synonymous single nucleotide polymorphism (SNP) rs1051730 on chromosome 15q25, in the gene for the nicotinic acetylcholine receptor (nAChr) subunit CHRNA3, showed the strongest association. For this SNP, which shows a risk allele frequency of approximately 38% in European populations, each copy of the risk allele corresponded to an increase in smoking quantity of 1 cigarette per day (CPD) 3. It is interesting that the cluster of genes on chromosome 15q25, encoding the nACHr subunits CHRNA5‐CHRNA3‐CHRNB4 , has been shown to be associated not only with smoking quantity and ND but also with smoking‐related diseases such as chronic obstructive pulmonary disease (COPD), lung cancer, peripheral artery disease and bladder cancer 7.…”

Does coffee consumption impact on heaviness of smoking?

“…The gene–exposure and gene–outcome associations were identified in the CCGC 8, TAG 15 and cotinine 16 consortia summary‐level data. Models 2 and 3 were included as sensitivity analyses, as recommended by Burgess and colleagues 14.…”

Different Effects of <i>TERT</i>, <i>TP</i>63, and <i>CYP</i>2<i>A</i>6 Polymorphism on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers

“…Recent association findings for nicotine dependence, smoking behavior, and smoking-related diseases implicate genetically derived individual differences [1][2][3][4][5]. Among several reports from genome-wide association studies (GWAS), nicotinic cholinergic receptor α (CHRNA3-CHRNA5, rs1051730 or rs667282) has been identified as a lung cancer susceptible locus [6][7][8].…”