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PLoS Genet. 2010 Aug 5;6(8). pii: e1001053. doi: 10.1371/journal.pgen.1001053.

Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.

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Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.


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.

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Conflict of interest statement

NLS is the spouse of S.F. Saccone, who is listed as an inventor on a patent, “Markers of Addiction”, covering the use of certain SNPs in diagnosing, prognosing, and treating addiction. LJB, JCW and JPR are listed as inventors on a patent, “Markers of Addiction,” covering the use of certain SNPs in diagnosing, prognosing, and treating addiction. LJB has served as a consultant to Pfizer in 2008. XK is a full time employee of GlaxoSmithKline. SP was a full time employee of GlaxoSmithKline. Current affiliation is with Hoffman-La Roche. JK has served as a consultant to Pfizer in 2008. MDL has served as a consultant to NIH, deCODE genetics, University of Pennsylvania, Reckitt Benckiser Pharmaceuticals, Pennsylvania Department of Health, and Informational Managements Consulting. Dr. Li also serves as a scientific advisor to ADial Pharmaceuticals. TJP receives compensation from the University of Mississippi Medical Center; part of his salary has been supported by grants from NIDA, NCI, the University of Mississippi Health Care Cancer Institute, the Mississippi State Department of Health, Pfizer Inc., and GlaxoSmithKline.

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