@article{6ff1e00d5b754f0180807391b7893065,
title = "Dissecting the genetic overlap of smoking behaviors, lung cancer, and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme",
abstract = "Smoking is a major contributor to lung cancer and chronic obstructive pulmonary disease (COPD). Two of the strongest genetic associations of smoking-related phenotypes are the chromosomal regions 15q25.1, encompassing the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4, and 19q13.2, encompassing the nicotine metabolizing gene CYP2A6. In this study, we examined genetic relations between cigarettes smoked per day, smoking cessation, lung cancer, and COPD. Data consisted of genome-wide association study summary results. Genetic correlations were estimated using linkage disequilibrium score regression software. For each pair of outcomes, z-score-z-score (ZZ) plots were generated. Overall, heavier smoking and decreased smoking cessation showed positive genetic associations with increased lung cancer and COPD risk. The chromosomal region 19q13.2, however, showed a different correlational pattern. For example, the effect allele-C of the sentinel SNP (rs56113850) within CYP2A6 was associated with an increased risk of heavier smoking (z-score = 19.2; p = 1.10 × 10−81), lung cancer (z-score = 8.91; p = 5.02 × 10−19), and COPD (z-score = 4.04; p = 5.40 × 10−5). Surprisingly, this allele-C (rs56113850) was associated with increased smoking cessation (z-score = −8.17; p = 2.52 × 10−26). This inverse relationship highlights the need for additional investigation to determine how CYP2A6 variation could increase smoking cessation while also increasing the risk of lung cancer and COPD likely through increased cigarettes smoked per day.",
keywords = "addiction, genetics, smoking, smoking cessation",
author = "Bray, {Michael J.} and Chen, {Li Shiun} and Louis Fox and Hancock, {Dana B.} and Culverhouse, {Robert C.} and Hartz, {Sarah M.} and Johnson, {Eric O.} and Mengzhen Liu and McKay, {James D.} and Saccone, {Nancy L.} and Hokanson, {John E.} and Vrieze, {Scott I.} and Tyndale, {Rachel F.} and Baker, {Timothy B.} and Bierut, {Laura J.}",
note = "Funding Information: The study was funded by the National Institutes of Health (NIH) Training Grant 5T32MH014677 to Michael J. Bray. This study was also funded by the NIH and National Institute of Drug Abuse Grants P30CA091842 and R01DA036583 to Laura J. Bierut and R01DA042090, R01DA044283 and R01DA037904 to Dana B. Hancock. Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism, R21AA024888. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. Rachel F. Tyndale acknowledges the support of a Canada Research Chair in Pharmacogenomics and CIHR (FDN‐154294). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institute of Health, Department of Health and Human Services, under contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I. The authors thank the staff and participants of the ARIC study for their important contributions. Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 and R01HG008983 (E. Boerwinkle). Funding Information: The study was funded by the National Institutes of Health (NIH) Training Grant 5T32MH014677 to Michael J. Bray. This study was also funded by the NIH and National Institute of Drug Abuse Grants P30CA091842 and R01DA036583 to Laura J. Bierut and R01DA042090, R01DA044283 and R01DA037904 to Dana B. Hancock. Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism, R21AA024888. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. Rachel F. Tyndale acknowledges the support of a Canada Research Chair in Pharmacogenomics and CIHR (FDN-154294). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institute of Health, Department of Health and Human Services, under contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I. The authors thank the staff and participants of the ARIC study for their important contributions. Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 and R01HG008983 (E. Boerwinkle). International Agency for Research on Cancer Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Publisher Copyright: {\textcopyright} 2020 Wiley Periodicals LLC",
year = "2020",
month = oct,
day = "1",
doi = "10.1002/gepi.22331",
language = "English",
volume = "44",
pages = "748--758",
journal = "Genetic Epidemiology",
issn = "0741-0395",
number = "7",
}