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Cited by 395Smoking Behavior and CessationGenetic Associations and EpidemiologyChronic Obstructive Pulmonary Disease (COPD) Research

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

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Saccone, Nancy L., Culverhouse, Robert C., Schwantes-An, Tae-Hwi, Cannon, Dale S., Chen, Xiangning, Cichon, Sven, Giegling, Ina, Han, Shizhong, Han, Younghun, Keskitalo-Vuokko, Kaisu, Kong, Xiangyang, Landi, Maria Teresa, Ma, Jennie Z., Short, Susan E., Stephens, Sarah H., Stevens, Victoria L., Sun, Lingwei, Wang, Yufei, Wenzlaff, Angela S., Aggen, Steven H., Breslau, Naomi, Broderick, Peter, Chatterjee, Nilanjan, Chen, Jingchun, Heath, Andrew C., Heliövaara, Markku, Hoft, Nicole R., Hunter, David J., Jensen, Majken K., Martin, Nicholas G., Montgomery, Grant W., Niu, Tianhua, Payne, Thomas J., Peltonen, Leena, Pergadia, Michele L., Rice, John P., Sherva, Richard, Spitz, Margaret R., Sun, Juzhong, Wang, Jen C., Weiss, Robert B., Wheeler, William, Witt, Stephanie H., Yang, Bao-Zhu, Caporaso, Neil E., Ehringer, Marissa A., Eisen, Tim, Gapstur, Susan M., Gelernter, Joel, Houlston, Richard, Kaprio, Jaakko, Kendler, Kenneth S., Kraft, Peter, Leppert, Mark F., Li, Ming D., Madden, Pamela A. F., Nöthen, Markus M., Pillai, Sreekumar, Rietschel, Marcella, Rujescu, Dan, Schwartz, Ann, Amos, Christopher I., Bierut, Laura J.·2010·PLoS Genetics
DOI 10.1371/journal.pgen.1001053PMC PMC2916847
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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.

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Figure 1 Forest plot for dichotomous CPD at locus 1 (tagging rs16969968). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age and sex as covariates. The box size indicates the precision of the OR estimate. The case and control totals include only individuals with a genotype call for locus 1. The heterogeneity p-value is 0.21.
Figure 1 Forest plot for dichotomous CPD at locus 1 (tagging rs16969968). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age and sex as covariates. The box size indicates the precision of the OR estimate. The case and control totals include only individuals with a genotype call for locus 1. The heterogeneity p-value is 0.21.CC0 · PubMed Central
Figure 2 Forest plot for dichotomous CPD at locus 2 (tagging rs578776). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age and sex as covariates. The heterogeneity p-value is 0.69.
Figure 2 Forest plot for dichotomous CPD at locus 2 (tagging rs578776). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age and sex as covariates. The heterogeneity p-value is 0.69.CC0 · PubMed Central
Figure 3 Forest plot for dichotomous CPD at locus 3 (tagging rs588765). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age and sex as covariates. The heterogeneity p-value is 0.59.
Figure 3 Forest plot for dichotomous CPD at locus 3 (tagging rs588765). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age and sex as covariates. The heterogeneity p-value is 0.59.CC0 · PubMed Central
Figure 4 Forest plot for lung cancer at locus 1 (tagging rs16969968). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age, sex and categorical CPD as covariates. The heterogeneity p-value is 0.86.
Figure 4 Forest plot for lung cancer at locus 1 (tagging rs16969968). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age, sex and categorical CPD as covariates. The heterogeneity p-value is 0.86.CC0 · PubMed Central
Figure 5 Forest plot for lung cancer at locus 2 (tagging rs578776). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age, sex and categorical CPD as covariates. The heterogeneity p-value is 0.44.
Figure 5 Forest plot for lung cancer at locus 2 (tagging rs578776). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age, sex and categorical CPD as covariates. The heterogeneity p-value is 0.44.CC0 · PubMed Central
Figure 6 Forest plot for lung cancer at locus 3 (tagging rs588765). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age, sex and categorical CPD as covariates. The heterogeneity p-value is 0.99.
Figure 6 Forest plot for lung cancer at locus 3 (tagging rs588765). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age, sex and categorical CPD as covariates. The heterogeneity p-value is 0.99.CC0 · PubMed Central
Figure 7 Forest plot for COPD at locus 1 (tagging rs16969968). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age, sex and categorical CPD as covariates. The heterogeneity p-value is 0.88.
Figure 7 Forest plot for COPD at locus 1 (tagging rs16969968). The ORs and 95% CIs are for the effect per allele using additive coding in the logistic regression with age, sex and categorical CPD as covariates. The heterogeneity p-value is 0.88.CC0 · PubMed Central

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Authors
Saccone, N. L., Culverhouse, R. C., Schwantes-An, T.-H., Cannon, D. S., Chen, X., Cichon, S., Giegling, I., Han, S., Han, Y., Keskitalo-Vuokko, K., Kong, X., Landi, M. T., Ma, J. Z., Short, S. E., Stephens, S. H., Stevens, V. L., Sun, L., Wang, Y., Wenzlaff, A. S., Aggen, S. H., Breslau, N., Broderick, P., Chatterjee, N., Chen, J., Heath, A. C., Heliövaara, M., Hoft, N. R., Hunter, D. J., Jensen, M. K., Martin, N. G., Montgomery, G. W., Niu, T., Payne, T. J., Peltonen, L., Pergadia, M. L., Rice, J. P., Sherva, R., Spitz, M. R., Sun, J., Wang, J. C., Weiss, R. B., Wheeler, W., Witt, S. H., Yang, B.-Z., Caporaso, N. E., Ehringer, M. A., Eisen, T., Gapstur, S. M., Gelernter, J., Houlston, R., Kaprio, J., Kendler, K. S., Kraft, P., Leppert, M. F., Li, M. D., Madden, P. A. F., Nöthen, M. M., Pillai, S., Rietschel, M., Rujescu, D., Schwartz, A., Amos, C. I., & Bierut, L. J.
Affiliations
  • Washington University in St. Louis (US)
  • University of Utah (US)
  • Virginia Commonwealth University (US)
  • University of Bonn (DE)
  • Ludwig-Maximilians-Universität München (DE)
  • Yale University (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • GlaxoSmithKline (United States) (US)
  • National Institutes of Health (US)
  • University of Virginia (US)
  • Harvard University (US)
  • University of Colorado Boulder (US)
  • American Cancer Society (US)
  • Institute of Cancer Research (GB)
  • Wayne State University (US)
  • Michigan State University (US)
  • Finnish Institute for Health and Welfare (FI)
  • QIMR Berghofer Medical Research Institute (AU)
  • University of Mississippi Medical Center (US)
  • Broad Institute (US)
  • Boston University (US)
  • Information Management Services (US)
  • Central Institute of Mental Health (DE)
  • NIHR Cambridge Biomedical Research Centre (GB)
  • University of Helsinki (FI)
Corresponding author
Saccone, Nancy L.
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2010-08-05
Volume
6
Issue
8
Pages
e1001053
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1001053
PMC
PMC2916847
OpenAlex
W2108344795
Cited by
395
References
72
Citations by year
2026: 3 · 2025: 4 · 2024: 7 · 2023: 12 · 2022: 15 · 2021: 23 · 2020: 17 · 2019: 9 · 2018: 20 · 2017: 23 · 2016: 43 · 2015: 34 · 2014: 48 · 2013: 40 · 2012: 53
FWCI
4.40
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • VCU Scholars Compass (Virginia Commonwealth University) (submittedVersion, public-domain)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • OpenBU (Boston University) (submittedVersion, other-oa)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Funders
  • American Cancer Society
  • Pfizer
  • GlaxoSmithKline (RES11080, SCO104960, SCO104960, NCT00292552, NCT00292552)
  • Pennsylvania Department of Health
  • Yale University
  • Wayne State University (P30 CA22453)
  • University of Pennsylvania
  • F. Hoffmann-La Roche
  • University of Minnesota
  • Henry Ford Health System (NO1-CN-25512)
  • Johns Hopkins University (HHSN268200782096C, U01HG004438, P01 CA089392)
  • University of Pittsburgh (NO1‐CN‐25511)
  • Georgetown University (NO1-CN-25522)
  • Wellcome Trust (201413, 129680, HEALTH-F4-2007-201413)
  • Broad Institute
  • Reckitt Benckiser Pharmaceuticals
  • Mississippi State Department of Health
  • Academy of Finland (129680)
  • Bundesministerium für Bildung und Forschung
  • Rheinische Friedrich-Wilhelms-Universität Bonn
  • National Institutes of Health (n01cn025516-044, n01cn025515-047, n01cn025513-043, n01cn025404-013, n01cn025514-038, n01cn025511-041, n01cn025524-036, n01cn075022-017, n01cn025476-008, n01cn025522-043, n01cn025512-050, n01cn025518-039, n01pc35145-19-0-7, 5p01dk070756-05, PC35145, CA- 016672, HHSN268200782096C, AA11998, CA089392, DA12854, DA011015)
  • University of California, Los Angeles (NO1-CN-25404)
  • University of Texas MD Anderson Cancer Center ((CA016672))
  • Gillings School of Public Health
  • University of Colorado Denver (NO1-CN-25514)
  • Medical Research Council (HHSN268200782096C)
  • National Health and Medical Research Council (DA019951)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA017889, AA11330, AA11998, AA015336, AA017889, K05AA017688, R01 AA13320, R01AA013321, P50AA011998, R01 AA11998, AA13320, AA13321, AA011949, R01 AA13321, R01AA011949, AA007464, HHSN268200782096C, 129680, R01AA011330, R01AA013320, K01AA015336, T32AA007464)
  • National Heart, Lung, and Blood Institute (HL72903, R01HL035464, HHSN268200782096C, P01HL072903, P01-HL72903, P01 HD31921)
  • National Institute on Drug Abuse (DA012845, R56DA012854, DA 019951, R03DA023166, R21DA027070, DA12844, DA13783, DA021913, DA-12849, DA 011015, R56 DA12854, K01DA019498, R01DA012845, R01-DA12844, P01-HD31921, DA12854, P60DA011015, DA12890, R01DA026911, R01DA12854, R21DA026901, K01DA024758, R01DA012844, R01 DA12890, DA026901, K02DA021237, DA021237, K08DA019951, DA023166, HHSN268200782096C, R01DA013783, R01DA012849, R01DA012854, R01 DA 13783, R01DA021913)
  • National Human Genome Research Institute (U01HG04424, U01HG004422, U01HG004399, U01HG004446, U01HG004424, U01HG004438, U01 HG04422-01, HG004446, HHSN268200782096C)
  • National Cancer Institute (R01CA127219, N01 CN25514, N01 CN025511, CA089392, N01-CN25404, CA55769, N01-CN-25 522, P30CA 22453, N01 CN-25524, R01CA060691, R01-CA87895, CA133996, CA-22453, CA 016672, N01-CN-25 476, N01 CN25515, N01 CN025516, N01 PC035145, R01CA133996, N01 CN025515, P01CA087969, N01 CN025514, N01 PC 35145, R01CA087895, P01CA089392, CA121197, R01 CA 60691, R01CA055769, N01CN25511, N01 CN025522, PC35145, CA60691, N01 CN025476, N01 CN025404, N01CN75022, R01CA121197, N01 CN025518, N01 CN025512, N01 CN025513, CA127219, N01 CN075022, CA87895, N01-CN-25513, N01 CN025524, P30CA016672, P30CA022453, N01 CN25512, N01CN25518, N01-CN-25 516)
  • National Institute of General Medical Sciences (CA016672, K25GM069590, GM69590, K25 GM69590)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P01-DK-070756, P01-HD31921, P30 CA22453, 5P01DK070756)
  • National Institute of Environmental Health Sciences (P30ES007784, R25ES011080)
  • National Institute of Child Health and Human Development (P01-HD31921)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 31921, P01- HD31921, P01HD031921, R24HD041020)
  • Carolina Population Center, University of North Carolina at Chapel Hill (P01HD31921)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
Keywords
smoking quantity, cigarettes per day, CHRNA5, CHRNA3, CHRNB4, nicotinic acetylcholine receptors, rs16969968, nicotine dependence, lung cancer, chronic obstructive pulmonary disease, genetic association
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Chromosomes, Human, Pair 15, Female, Humans, Lung Neoplasms, Male, Middle Aged, Nerve Tissue Proteins, Receptors, Nicotinic, Smoking, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, White People, Young Adult

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