Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Andries T Marees; Anke R Hammerschlag; Lisa Bastarache; Hilde de Kluiver; Florence Vorspan; Wim van den Brink; Dirk J Smit; Damiaan Denys; Eric R Gamazon; Ruifang Li-Gao; Elemi J Breetvelt; Mark C H de Groot; Tessel E Galesloot; Sita H Vermeulen; Jan L Poppelaars; Patrick C Souverein; Renske Keeman; Renée de Mutsert; Raymond Noordam; Frits R Rosendaal; Najada Stringa; Dennis O Mook-Kanamori; Ilonca Vaartjes; Lambertus A Kiemeney; Martin den Heijer; Natasja M van Schoor; Olaf H Klungel; Anke H Maitland-Van der Zee; Marjanka K Schmidt; Tinca J C Polderman; Andries R van der Leij; Danielle Posthuma; Eske M Derks

doi:10.1016/j.drugalcdep.2018.03.026

Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Drug Alcohol Depend. 2018 Jul 1:188:94-101. doi: 10.1016/j.drugalcdep.2018.03.026. Epub 2018 Apr 25.

Authors

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

Affiliations

¹ Department of Psychiatry, Amsterdam Neuroscience, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; QIMR Berghofer, Translational Neurogenomics Group, Brisbane, Australia. Electronic address: [email protected].
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.

PMID: 29758381
DOI: 10.1016/j.drugalcdep.2018.03.026

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.

Keywords: Addiction; Alcohol; Exome; Nicotine; PRS; Pathway analysis; Rare variants; Tobacco.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Alcohol Drinking / epidemiology
Alcohol Drinking / genetics*
Alcoholism / diagnosis
Alcoholism / epidemiology
Alcoholism / genetics
Cohort Studies
Exons / genetics*
Female
Genetic Predisposition to Disease / epidemiology
Genetic Predisposition to Disease / genetics*
Genetic Variation / genetics*
Humans
Male
Nerve Tissue Proteins / genetics
Polymorphism, Single Nucleotide / genetics
Receptors, Nicotinic / genetics
Risk Factors
Tobacco Use / epidemiology
Tobacco Use / genetics*
Tobacco Use Disorder / diagnosis
Tobacco Use Disorder / genetics

Substances

Nerve Tissue Proteins
Receptors, Nicotinic