Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.
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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
Аннотация
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.