Journal
PLOS GENETICS
Volume 6, Issue 8, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1001053
Keywords
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Categories
Funding
- National Institute on Drug Abuse (NIDA) [R01 DA026911, R03 DA023166, K02 DA021237, R21 DA026901, P60 DA011015, R01 DA012845, R01 DA021913, R01 DA12854, K01DA019498, R21DA027070, R01s DA12890, DA12849, K01DA024758, R01 DA-12844, R01 DA-13783]
- National Institute of General Medical Sciences (NIGM) [K25 GM69590]
- American Cancer Society (ACS) [IRG-58-010-50]
- National Cancer Institute (NCI) [P01 CA089392, CA55769, CA121197, CA133996, CA016672, CA127219, R01 CA60691, R01 CA87895, N01 PC35145, P30 CA22453, P01CA087969, NO1-CN-25514]
- The National Human Genome Research Institute (NHGRI) [U01 HG04422-01, HHSN271200477471C, HHSN271200477451C, 5U01HG004399]
- National Institutes of Health [HHSN268200782096]
- NIDA/NHLBI [P01-HL72903]
- GlaxoSmithKline [SCO104960, NCT00292552, RES11080]
- National Institute of Environmental Health (NIEH) [P30ES007784]
- NIAAA [K01 AA015336, R01 AA017889, T32 AA007464, R01 AA011949, AA11330]
- NICHD [P01 HD31921]
- Center of Excellence in Complex Disease Genetics of the Academy of Finland [21356, 129680]
- European Community [HEALTH-F4-2007-201413]
- Nordic Center of Excellence in Disease Genetic
- Wellcome Trust
- NIDDK [5P01DK070756]
- NHLBI [5R01HL035464]
- Merck Research Laboratories
- German Federal Ministry of Education and Research (BMBF) [01GS8152]
- NIH, NCI, Division of Cancer Epidemiology and Genetics
- Georgetown University [NO1-CN-25522]
- Pacific Health Research Institute [NO1-CN-25515]
- Henry Ford Health System [NO1-CN-25512]
- University of Minnesota [NO1-CN-25513]
- Washington University [NO1-CN-25516]
- University of Pittsburgh [NO1-CN-25511]
- University of Utah [NO1 CN-25524]
- Marshfield Clinic Research Foundation [NO1-CN-25518]
- University of Alabama at Birmingham [NO1 CN-75022]
- Westat, Inc. [NO1-CN-25476]
- University of California, Los Angeles [NO1-CN-25404]
- Environment and Health Initiative
- GENEVA Coordinating Center [U01 HG004446]
- NIH GEI [U01HG004438, U01HG04424]
- NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' [HHSN268200782096C]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01-HD31921]
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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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