Andries T Marees1, Anke R Hammerschlag2, Lisa Bastarache3, Hilde de Kluiver4, Florence Vorspan5, Wim van den Brink6, Dirk J Smit6, Damiaan Denys6, Eric R Gamazon7, Ruifang Li-Gao8, Elemi J Breetvelt9, Mark C H de Groot10, Tessel E Galesloot11, Sita H Vermeulen11, Jan L Poppelaars12, Patrick C Souverein13, Renske Keeman14, Renée de Mutsert8, Raymond Noordam15, Frits R Rosendaal8, Najada Stringa16, Dennis O Mook-Kanamori17, Ilonca Vaartjes18, Lambertus A Kiemeney11, Martin den Heijer19, Natasja M van Schoor16, Olaf H Klungel13, Anke H Maitland-Van der Zee20, Marjanka K Schmidt14, Tinca J C Polderman2, Andries R van der Leij21, Danielle Posthuma22, Eske M Derks23. 1. Department of Psychiatry, Amsterdam Neuroscience, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; QIMR Berghofer, Translational Neurogenomics Group, Brisbane, Australia. Electronic address: andriestm@hotmail.com. 2. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. 3. Center for Precision Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, United States. 4. GGZ inGeest and Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands. 5. Assistance Publique-Hôpitaux de Paris, Hôpital Fernand Widal, Département de Psychiatrie et de Médecine Addictologique, 200 Rue du Faubourg Saint-Denis, Paris, France; Inserm umr-s 1144, Université Paris Descartes, Université Paris Diderot, 4 Avenue de l'Observatoire, Paris, France. 6. Department of Psychiatry, Amsterdam Neuroscience, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 7. Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; Clare Hall, University of Cambridge, Cambridge, CB3 9AL, United Kingdom. 8. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 9. The Dalglish Family 22q Clinic, Toronto General Hospital, University Health Network, Toronto, Canada; Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Canada. 10. Department of Clinical Chemistry and Haematology, Division of Laboratory and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands. 11. Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 12. Department of Sociology, VU University, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands. 13. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. 14. Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 15. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. 16. Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands. 17. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands. 18. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. 19. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. 20. Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 21. Department of Brain and Cognition, University of Amsterdam, Amsterdam, The Netherlands. 22. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. 23. Department of Psychiatry, Amsterdam Neuroscience, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; QIMR Berghofer, Translational Neurogenomics Group, Brisbane, Australia.
Abstract
BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.
BACKGROUND:Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.
Authors: Kirsha S Gordon; Kathleen McGinnis; Cecilia Dao; Christopher T Rentsch; Aeron Small; Rachel Vickers Smith; Rachel L Kember; Joel Gelernter; Henry R Kranzler; Kendall J Bryant; Janet P Tate; Amy C Justice Journal: AIDS Behav Date: 2020-02
Authors: Victoria A Risner; Chelsie E Benca-Bachman; Lauren Bertin; Alicia K Smith; Jaakko Kaprio; John E McGeary; Elissa Chesler; Valerie S Knopik; Naomi P Friedman; Rohan H C Palmer Journal: Nicotine Tob Res Date: 2021-11-05 Impact factor: 4.244