Genome-wide and candidate gene association study of cigarette smoking behaviors.
paper
Cited
Public
- Authors
- Caporaso, Neil; Gu, Fangyi; Chatterjee, Nilanjan; Sheng-Chih, Jin; Yu, Kai; Yeager, Meredith; Chen, Constance; Jacobs, Kevin; Wheeler, William; Landi, Maria Teresa; Ziegler, Regina G; Hunter, David J; Chanock, Stephen; Hankinson, Susan; Kraft, Peter; Bergen, Andrew W
- Year
- 2009
- Journal
- PloS one
- PMID
- 19247474
- DOI
- 10.1371/journal.pone.0004653
- PMCID
- PMC2644817
The contribution of common genetic variation to one or more established smoking behaviors was investigated in a joint analysis of two genome wide association studies (GWAS) performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project in 2,329 men from the Prostate, Lung, Colon and Ovarian (PLCO) Trial, and 2,282 women from the Nurses' Health Study (NHS). We analyzed seven measures of smoking behavior, four continuous (cigarettes per day [CPD], age at initiation of smoking, duration of smoking, and pack years), and three binary (ever versus never smoking, < or = 10 versus > 10 cigarettes per day [CPDBI], and current versus former smoking). Association testing for each single nucleotide polymorphism (SNP) was conducted by study and adjusted for age, cohabitation/marital status, education, site, and principal components of population substructure. None of the SNPs achieved genome-wide significance (p<10(-7)) in any combined analysis pooling evidence for association across the two studies; we observed between two and seven SNPs with p<10(-5) for each of the seven measures. In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10(-3)), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk. In parallel, we selected 11,199 SNPs drawn from 359 a priori candidate genes and performed individual-gene and gene-group analyses. After adjusting for multiple tests conducted within each gene, we identified between two and five genes associated with each measure of smoking behavior. Besides CHRNA3 and CHRNA5, MAOA was associated with CPDBI (gene-level p<5.4x10(-5)), our analysis provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior that merit further follow-up.
βlog10 p-values for association with seven continuous (Figure 1) and categorical (Figure 2) smoking behaviors.P-values are based on the combined evidence for association from both PLCO and NHS.
βlog10 p-values for association with seven continuous (Figure 1) and categorical (Figure 2) smoking behaviors.P-values are based on the combined evidence for association from both PLCO and NHS.
βlog10 p-values for association with number of cigarettes smoked per day (CPD) for SNPs in the chr15q25.1 region.P-values are based on the combined evidence for association from both PLCO and NHS. Filled symbols denote genotyped SNPs; open symbols denote imputed SNPs. Black diamonds (squares) denote SNPs associated with continuous (binary) CPD in previous reports. Red circles denote SNPs associated with lung cancer in previous reports.
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| Name | Type |
|---|---|
| ADH4 | gene |
| ADH6 | gene |
| African American | cohort |
| age at initiation | phenotype |
| age at initiation of smoking local | phenotype |
| age of onset | phenotype |
| alcohol | phenotype |
| alcohol dehydrogenase | gene |
| alcoholism | phenotype |
| Asian | cohort |
| binary trait | phenotype |
| breast cancer | phenotype |
| Cancer Genetic Markers of Susceptibility local | cohort |
| Cancer Genetic Markers of Susceptibility (CGEMS) local | cohort |
| catecholamines | drug |
| cell cycle control local | gene |
| CGEMS local | cohort |
| chr15q25.1 local | drug |
| chr15q25.1 region local | gene |
| CHRNA1 | gene |
| Chrna3 | gene |
| CHRNA5 | gene |
| Chrnb4 | gene |
| cigarettes | phenotype |
| CIGSTAT local | phenotype |
| continuous phenotype | phenotype |
| CPD | phenotype |
| CPDBI local | phenotype |
| CTNNA3 | gene |
| current smoking | phenotype |
| Current versus Former smoking status local | phenotype |
| CYP2A6 | gene |
| CYP2B6 | gene |
| cytochrome P450 | gene |
| DGK1 local | gene |
| dopamine | drug |
| drug metabolizing enzyme local | gene |
| DSM-IV nicotine dependence | phenotype |
| Duration | phenotype |
| duration of smoking | phenotype |
| EIGENSTRAT | drug |
| European ancestry | cohort |
| European population | cohort |
| Ever never smoking local | phenotype |
| Ever-Never smoking status local | phenotype |
| ever smokers local | phenotype |
| Ever-smokers local | phenotype |
| ever smoking | phenotype |
| EVNV local | phenotype |
| Fagerstrom Test for Nicotine Dependence (FTND) local | phenotype |
| Fagerstrom Test for Nicotine Dependence (FTQ) local | phenotype |
| FBXL17 local | gene |
| Female smokers local | cohort |
| Feng et al., 2006 local | cohort |
| FNTD local | phenotype |
| former smokers | phenotype |
| Former smoking status local | phenotype |
| FTND | phenotype |
| FTO | gene |
| HapMap3 | cohort |
| HapMap CEU | cohort |
| HapMap CHB+JPT local | cohort |
| Heaviness Smoking Index local | phenotype |
| heavy smoking | phenotype |
| lung cancer | phenotype |
| Male smokers local | cohort |
| MAOA | gene |
| MAOB | gene |
| muscarinic receptor local | gene |
| NFKB1 | gene |
| NHS | cohort |
| NHS sample local | cohort |
| nicotine | drug |
| nicotine dependence | phenotype |
| nicotine metabolism | phenotype |
| nicotine related behaviors local | phenotype |
| nicotinic acetylcholine receptor | drug |
| nicotinic cholinergic receptors local | gene |
| nicotinic receptors local | gene |
| Nicotinic Receptors local | gene |
| NICSNP study local | cohort |
| non-European ancestry | cohort |
| NRX1 local | gene |
| opioid | drug |
| pack-years | phenotype |
| Parkinson's disease | phenotype |
| PBX2 local | gene |
| PKYRS local | phenotype |
| PLCO | cohort |
| PLCO sample local | cohort |
| population stratification | phenotype |
| prostate cancer | phenotype |
| Prostate, Lung, Colon and Ovarian Trial local | cohort |
| PSMA4 | gene |
| pulmonary chemoreflex response local | phenotype |
| quit status local | phenotype |
| reward deficiency syndrome | phenotype |
| RORB | gene |
| rs10489113 local | variant |
| rs1051730 | variant |
| rs10793832 local | variant |
| rs1433050 local | variant |
| rs16969968 | variant |
| rs2036527 | variant |
| rs3027409 local | variant |
| rs3828541 local | variant |
| rs3857224 local | variant |
| rs578776 | variant |
| rs6437740 local | variant |
| rs7050529 local | variant |
| rs8034191 | variant |
| rs885624 local | variant |
| Saccone et al., 2007 local | cohort |
| serotonin | drug |
| SLCO3A1 | gene |
| SMKAGE local | phenotype |
| SMKDU local | phenotype |
| smoking | phenotype |
| smoking behavior | phenotype |
| smoking behavior EVNV local | phenotype |
| smoking behaviors | phenotype |
| smoking cessation | phenotype |
| smoking initiation | phenotype |
| smoking intensity | phenotype |
| smoking phenotypes | phenotype |
| SNP | cohort |
| SNP allele local | variant |
| SNPs in 15q25.1 local | variant |
| Structure | drug |
| study cohort | cohort |
| tobacco dependence | phenotype |
| tobacco smoke | phenotype |
| tobacco use | phenotype |
| Transient Receptor Potential cation family local | gene |
| TRPC5 local | gene |
| TRPC7 local | gene |
| TRPC subfamily local | gene |
| TRPV subfamily local | gene |
| U.S. non-Hispanic whites local | cohort |
| vanilloid subfamily local | gene |
| voltage-dependent calcium-activated potassium channels local | gene |
| Voltage-Dependent Calcium-Activated Potassium Channels local | gene |
| VPS13A local | gene |
| withdrawal severity | phenotype |
| women | cohort |
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