Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use
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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Advisors
Supervisors
Document Type
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, Exome, Rare variants, Tobacco, Nicotine, Alcohol, PRS, Pathway analysis, SDG 3 - Good Health and Well-being
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