TY - JOUR
T1 - Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use
AU - Marees, Andries T.
AU - Hammerschlag, Anke R.
AU - Bastarache, Lisa
AU - de Kluiver, Hilde
AU - Vorspan, Florence
AU - van den Brink, Wim
AU - Smit, Dirk J.
AU - Denys, Damiaan
AU - Gamazon, Eric R.
AU - Li-Gao, Ruifang
AU - Breetvelt, Elemi J.
AU - de Groot, Mark C.H.
AU - Galesloot, Tessel E.
AU - Vermeulen, Sita H.
AU - Poppelaars, Jan L.
AU - Souverein, Patrick C.
AU - Keeman, Renske
AU - de Mutsert, Renée
AU - Noordam, Raymond
AU - Rosendaal, Frits R.
AU - Stringa, Najada
AU - Mook-Kanamori, Dennis O.
AU - Vaartjes, Ilonca
AU - Kiemeney, Lambertus A.
AU - den Heijer, Martin
AU - van Schoor, Natasja M.
AU - Klungel, Olaf H.
AU - Maitland-Van der Zee, Anke H.
AU - Schmidt, Marjanka K.
AU - Polderman, Tinca J.C.
AU - van der Leij, Andries R.
AU - Posthuma, Danielle
AU - Derks, Eske M.
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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.
AB - 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.
KW - Addiction
KW - Alcohol
KW - Exome
KW - Nicotine
KW - Pathway analysis
KW - PRS
KW - Rare variants
KW - Tobacco
UR - https://www.scopus.com/pages/publications/85046793831
U2 - 10.1016/j.drugalcdep.2018.03.026
DO - 10.1016/j.drugalcdep.2018.03.026
M3 - Article
C2 - 29758381
SN - 0376-8716
VL - 188
SP - 94
EP - 101
JO - Drug and Alcohol Dependence
JF - Drug and Alcohol Dependence
ER -