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Dissecting the genetic overlap of smoking behaviors,lung cancer,and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme |
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| Authors: | Michael J. Bray Li-Shiun Chen Louis Fox Dana B. Hancock Robert C. Culverhouse Sarah M. Hartz Eric O. Johnson Mengzhen Liu James D. McKay Nancy L. Saccone John E. Hokanson Scott I. Vrieze Rachel F. Tyndale Timothy B. Baker Laura J. Bierut |
| Affiliation: | 1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri;2. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri;3. GenOmics, Bioinformatics, and Translational Research Center, Biostatistics & Epidemiology Division, RTI International, Research Triangle Park, North Carolina;4. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri;5. GenOmics, Bioinformatics, and Translational Research Center, Biostatistics & Epidemiology Division, RTI International, Research Triangle Park, North Carolina Fellow Program, RTI International, Research Triangle Park, North Carolina;6. Department of Psychology, University of Minnesota, Minneapolis, Minnesota;7. International Agency for Research on Cancer, World Health Organization, Lyon, France;8. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri;9. Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado;10. Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada Department of Pharmacology & Toxicology, and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;11. Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin |
| 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 |