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DOI 10.1016/j.drugalcdep.2018.03.026

Медицинская библиотека · Drug and alcohol dependence · 2018

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

СтатьяМетаанализПоддержка исследования: вне правительства СШАПеревод пока не подготовлен

Аннотация

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.

Для цитирования: 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. Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.. Drug and alcohol dependence. 2018. DOI: 10.1016/j.drugalcdep.2018.03.026.

Предметные рубрики MeSH

Alcohol DrinkingAlcoholismCohort StudiesExonsFemaleGenetic Predisposition to DiseaseGenetic VariationHumansMaleNerve Tissue ProteinsPolymorphism, Single NucleotideReceptors, NicotinicRisk FactorsTobacco UseTobacco Use Disorder
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