Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD

Abstract

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10−35 and <10−8 respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10−6). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10−20) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

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.…”

Beyond Cigarettes Per Day. A Genome-Wide Association Study of the Biomarker Carbon Monoxide

“…The direction of effect is as expected given the previous association with heaviness of smoking. In European ancestry populations, this variant is highly correlated with rs1051730 in CHRNA3 (r 2 = 1) and rs8031948 in ADGPH1 (r 2 = 0.934), which, in addition to rs16969968, have been previously associated with smoking behavior, COPD, and lung cancer (4,(33)(34)(35). The SNP most significantly associated with CO, rs55958997 (b = 2.75; 95% CI, 1.86-3.64; P = 1.60 3 10 29 ), is also in high linkage disequilibrium with rs16969968 (r 2 = 0.82) in Europeans (36).…”

Different Effects of &lt;i&gt;TERT&lt;/i&gt;, &lt;i&gt;TP&lt;/i&gt;63, and &lt;i&gt;CYP&lt;/i&gt;2&lt;i&gt;A&lt;/i&gt;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].…”