Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use
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; Breetvelt, Elemi J; de Groot, Mark C H; Galesloot, Tessel E; Vermeulen, Sita H; Poppelaars, Jan L; Souverein, Patrick C; Keeman, Renske; de Mutsert, Renée; Noordam, Raymond; Rosendaal, Frits R; Stringa, Najada; Mook-Kanamori, Dennis O; Vaartjes, Ilonca; Kiemeney, Lambertus A; den Heijer, Martin; van Schoor, Natasja M; Klungel, Olaf H; Maitland-Van der Zee, Anke H; Schmidt, Marjanka K; Polderman, Tinca J C; van der Leij, Andries R; Posthuma, Danielle; Derks, Eske M
(2018) Drug and Alcohol Dependence, volume 188, pp. 94 - 101
(Article)
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:
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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.
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Keywords: Addiction, Exome, Rare variants, Tobacco, Nicotine, Alcohol, PRS, Pathway analysis
ISSN: 0376-8716
Publisher: Elsevier Ireland Ltd.
Note: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
(Peer reviewed)