Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD
Year: 2010
Type: review
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.
Source: PLoS Genetics
Authors: Nancy L. Saccone, Robert C. Culverhouse, Tae-Hwi Schwantes-An, Dale S. Cannon, Xiangning Chen, Sven Cichon, Ina Giegling, Shizhong Han, Younghun Han, Kaisu Keskitalo-Vuokko, Xiangyang Kong, Maria Teresa Landi, Jennie Z. Ma, Susan E. Short, Sarah H. Stephens, Victoria L. Stevens, Lingwei Sun, Yufei Wang, Angela S. Wenzlaff, Steven H. Aggen, Naomi Breslau, Peter Broderick, Nilanjan Chatterjee, Jingchun Chen, Andrew C. Heath, Markku Heliövaara, Nicole R. Hoft, David J. Hunter, Majken K. Jensen, Nicholas G. Martin, Grant W. Montgomery, Tianhua Niu, Thomas J. Payne, Leena Peltonen, Michele L. Pergadia, John P. Rice, Richard Sherva, Margaret R. Spitz, Juzhong Sun, Jen C. Wang, Robert B. Weiss, William Wheeler, Stephanie H. Witt, Bao-Zhu Yang, Neil E. Caporaso, Marissa A. Ehringer, Tim Eisen, Susan M. Gapstur, Joel Gelernter, Richard Houlston, Jaakko Kaprio, Kenneth S. Kendler, Peter Kraft, Mark F. Leppert, Ming D. Li, Pamela A. F. Madden, Markus M. Nöthen, Sreekumar Pillai, Marcella Rietschel, Dan Rujescu, Ann Schwartz, Christopher I. Amos, Laura J. Bierut
Institutions: Washington University in St. Louis, University of Utah, Virginia Commonwealth University, University of Bonn, Forschungszentrum Jülich, Life & Brain (Germany), Ludwig-Maximilians-Universität München, Yale University, The University of Texas MD Anderson Cancer Center, University of Helsinki, GlaxoSmithKline (United States), National Institutes of Health, Division of Cancer Epidemiology and Genetics, University of Virginia, Harvard University, Brown University, University of Colorado Boulder, American Cancer Society, Institute of Cancer Research, Wayne State University, The Barbara Ann Karmanos Cancer Institute, Michigan State University, Finnish Institute for Health and Welfare, QIMR Berghofer Medical Research Institute, University of Mississippi Medical Center, Broad Institute, Wellcome Sanger Institute, Institute for Molecular Medicine Finland, Massachusetts Institute of Technology, Boston University, Information Management Services, Central Institute of Mental Health, NIHR Cambridge Biomedical Research Centre
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: American Cancer Society, Pfizer, GlaxoSmithKline, Pennsylvania Department of Health, Yale University, Wayne State University, University of Pennsylvania, F. Hoffmann-La Roche, University of Minnesota, Henry Ford Health System, Johns Hopkins University, University of Pittsburgh, Georgetown University, Wellcome Trust, Broad Institute, Reckitt Benckiser Pharmaceuticals, Mississippi State Department of Health, Academy of Finland, Bundesministerium für Bildung und Forschung, Rheinische Friedrich-Wilhelms-Universität Bonn, National Institutes of Health, University of California, Los Angeles, University of Texas MD Anderson Cancer Center, Gillings School of Public Health, University of Colorado Denver, Medical Research Council, National Health and Medical Research Council, National Institute on Alcohol Abuse and Alcoholism, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Carolina Population Center, University of North Carolina at Chapel Hill
Awards: G1064350653, G1104044120, PROSTATE, LUNG, COLORECTAL &OVARIAN (PLCO) CANCER, G111615301, G1129713815, PROSTATE, LUNG, COLORECTAL AND OVARIAN CANCER, G1165640160, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, G1267016694, G1270179341, G1271251741, G1285883624, The Genetics of Vulnerability to Nicotine Addictions, G1392149532, G1394878971, G1398898637, G142049768, G1425089079, G1425959741, G1468253849, G148520442, G1520690021, G1548154123, G1578565442, G1717613936, G1738478728, PROSTATE, LUNG, COLORECTAL, AND OVARIAN (PLCO) CANCER, G180930151, Variants in CHRNA5/CHRNA3/CHRNB4 and nicotine dependence, Genetic Epidemiology of Lung Cancer, G1848479244, G1869139066, G187063468, G1876780871, G1895444557, G1901027039, G1915609946, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, G1921953589, G1961596689, G1978181597, G2069664613, G2070044820, G2146332128, G2244524868, G2248614246, G2250436683, G226397431, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, G2382756871, G238373470, G2403188190, G2407800586, G2428068543, G2468562894, G2561471519, G265864768, Study of Addiction: Genetics and Environment, G2769583689, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, PROSTATE, LUNG, COLORECTAL, &OVARIAN CANCER SCREENING, G2848247982, Genes and Environment Initiatives in Type 2 Diabetes, G286522202, G288697090, PROSTATE, LUNG, COLORECTAL &OVARIAN CANCER, PROSTATE, LUNG, COLORECTAL AND OVARIAN CANCER, G3166288362, G3193254293, G3245180032, G3373150819, MARC: Genetic Epidemiology of Alcoholism & Comorbidity, G3446191057, G3532200029, G3548961933, Dietary Etiologies of Heart Disease, G3619332945, G370871742, G3745678260, G3749521157, G3799582765, G3846322534, Dietary and Hormonal Determinants of Cancer in Women, G3986927127, G4060863596, G407014587, G4095987353, G412057792, G420024314, G4214044282, G4230088115, G4248301501, G425717312, PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER, G4471409110, G4503763930, G4509978856, G4522106329, G452865728, Genome Wide Association Coordinating Center, HUMAN GENETIC VARIATION IN SMOKING AND ADDICTION RISK, G4764582563, G4775479183, G4808091200, G490693365, G4922896994, G4961133417, G5058729078, G506888700, G5069178581, G5107449428, G5198629111, SEER RRSS #4: Cancer in Arab American Estimating Rates and Fostering Research, Mapping Genes for comorbidity of SUDs and Depression, G5307852374, G5424457750, G5483271793, Mechanisms and Prevention of Environmental Disease, The Pathobiology of Nephrolithiasis, G5604691739, G5611356387, Fine Mapping Susceptibility Loci for Nicotine Dependence, G5692528997, G6050486683, G6129226368, G6134854566, G6150611542, G616188461, G6177097893, G6219625355, G6229538190, G6272369800, G6375054419, R24 Population Center Grant, G6447057531, G6525491790, G6529523796, Genetics of Alcohol Dependence in American Populations, G6665223695, G668214460, High Density Association Analysis of Lung Cancer, G6736661663, G6805771453, G7002240042, G7086035890, G7093047072, G7195761885, G7319620556, G7400349024, G7421337856, G7442572985, G7522350138, G754838926, G7582978137, G7623829690, G7669442478, G7732665852, G7761437327, G7928935416, G7949433598, G8016623132, G8161118679, G8267674335, Genetics of Cocaine Dependence, G8312728332, G8315719417, G840131496, G840737594, G8435153614, G8509316824, G858805679, G8718816475, G8779995270, G886698072, G88852782, G9000006138, G9000009355, G9000010803, G9000039457, G9000054071, G9000078609, G9000093746, G9000110938, G9000122333, G9000134904, G9000144364, G9000157960, G9000176579, G9000204396, G9000243987, G9000257263, G9000309104, G9000311153, Cancer Center Support Grant, CANCER CENTER SUPPORT GRANT, G938551828, Genetics of Adolescent Antisocial Drug Dependence, G957887912, G963041396, G979407967, G996329585
OpenAlex ID: W2108344795