Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use
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Publication date
2018-07-01
Authors
Marees, Andries T.
Hammerschlag, Anke R.
Bastarache, Lisa
de Kluiver, Hilde
Vorspan, Florence
van den Brink, Wim
Smit, Dirk J.
Denys, Damiaan
Gamazon, Eric R.
Li-Gao, Ruifang
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Article
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cc_by_nc_nd
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, Pathway analysis, PRS, Rare variants, Tobacco, Toxicology, Pharmacology, Psychiatry and Mental health, Pharmacology (medical)
Citation
Marees, A T, Hammerschlag, A R, Bastarache, L, de Kluiver, H, Vorspan, F, van den Brink, W, Smit, D J, Denys, D, Gamazon, E R, Li-Gao, R, Breetvelt, E J, de Groot, M C H, Galesloot, T E, Vermeulen, S H, Poppelaars, J L, Souverein, P C, Keeman, R, de Mutsert, R, Noordam, R, Rosendaal, F R, Stringa, N, Mook-Kanamori, D O, Vaartjes, I, Kiemeney, L A, den Heijer, M, van Schoor, N M, Klungel, O H, Maitland-Van der Zee, A H, Schmidt, M K, Polderman, T J C, van der Leij, A R, Posthuma, D & Derks, E M 2018, 'Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use', Drug and Alcohol Dependence, vol. 188, pp. 94-101. https://doi.org/10.1016/j.drugalcdep.2018.03.026