Abstract
Molecular mechanisms that prompt or mitigate excessive alcohol consumption could be partly explained by metabolic shifts. This genome-wide association study aims to identify the susceptibility gene loci for excessive alcohol consumption by jointly measuring weekly alcohol consumption and γ-GT levels. We analysed the Taiwan Biobank data of 18,363 Taiwanese people, including 1945 with excessive alcohol use. We found that one or two copies of the G allele in rs671 (ALDH2) increased the risk of excessive alcohol consumption, while one or two copies of the C allele in rs3782886 (BRAP) reduced the risk of excessive alcohol consumption. To minimize the influence of extensive regional linkage disequilibrium, we used the ridge regression. The ridge coefficients of rs7398833, rs671 and rs3782886 were unchanged across different values of the shrinkage parameter. The three variants corresponded to posttranscriptional activity, including cut-like homeobox 2 (a protein coded by CUX2), Glu504Lys of acetaldehyde dehydrogenase 2 (a protein encoded by ALDH2) and Glu4Gly of BRCA1-associated protein (a protein encoded by BRAP). We found that Glu504Lys of ALDH2 and Glu4Gly of BRAP are involved in the negative regulation of excessive alcohol consumption. The mechanism underlying the γ-GT-catalytic metabolic reaction in excessive alcohol consumption is associated with ALDH2, BRAP and CUX2. Further study is needed to clarify the roles of ALDH2, BRAP and CUX2 in the liver–brain endocrine axis connecting metabolic shifts with excessive alcohol consumption.
Highlights
Molecular mechanisms that prompt or mitigate excessive alcohol consumption could be partly explained by metabolic shifts
We retrieved data on the whole-genome genotyping, and the levels of serum γ-glutamyl transpeptidase (γ-GT) and medical history of the 18,363 people whose information had been held in the Taiwan Biobank (TWB)
Our main finding is that in excessive alcohol consumption, the γ-GT-catalytic reaction is associated with acetaldehyde dehydrogenase 2 (ALDH2), BRAP7. We found that rs3782886 (BRAP) and CUX2
Summary
Molecular mechanisms that prompt or mitigate excessive alcohol consumption could be partly explained by metabolic shifts This genome-wide association study aims to identify the susceptibility gene loci for excessive alcohol consumption by jointly measuring weekly alcohol consumption and γ-GT levels. The mechanism underlying the γ-GT-catalytic metabolic reaction in excessive alcohol consumption is associated with ALDH2, BRAP and CUX2. Further study is needed to clarify the roles of ALDH2, BRAP and CUX2 in the liver–brain endocrine axis connecting metabolic shifts with excessive alcohol consumption. The largest study of GWAS on tobacco and alcohol uses involved 1.2 million individuals and uncovered genetic bearing of ADH1B and GCKR, suggesting that alcohol consumption is influenced by individual differences in one’s ability to process calorie-rich alcoholic b everages[9]. The “go pathways” are signalling cascades that contribute to the transition from moderate to excessive alcohol intake, including activation of protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II, whereas the “stop pathways” keep alcohol intake in check, by upregulation of brain-derived neurotropic factor (BDNF) and glial cell line-derived neurotropic factor (GDNF)[14]
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