Clarke T-K, Adams M J, Davies G, Howard D M, Hall L S, Padmanabhan S, Murray A D, Smith B H, Campbell A, Hayward C, Porteous D J, Deary I J, McIntosh A M
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Mol Psychiatry. 2017 Oct;22(10):1376-1384. doi: 10.1038/mp.2017.153. Epub 2017 Jul 25.
Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.
饮酒已与200多种疾病相关联，并且造成了全球超过5%的疾病负担。酒精代谢基因中的知名遗传变异，例如乙醛脱氢酶2（ALDH2）和乙醇脱氢酶1B（ADH1B），与饮酒密切相关，但在欧洲人群中，这些变异出现的频率较低，影响有限。我们对英国生物银行（UKB）中112117名英国白人个体自我报告的饮酒情况进行了全基因组关联研究（GWAS）。我们报告了在14个基因座上存在全基因组显著关联。这些基因座包括酒精代谢基因（ADH1B/ADH1C/ADH5）中的单核苷酸多态性（SNP）以及KLB基因中的两个基因座，KLB是最近发现与饮酒相关的一个基因。我们还在包括葡萄糖激酶调节蛋白（GCKR）、细胞粘附分子2（CADM2）和家族性神经疾病相关蛋白69C（FAM69C）等新基因座上鉴定出了SNP。基于基因的分析发现，与物质使用神经生物学相关的基因（多巴胺受体D2（DRD2）、磷酸二酯酶4B（PDE4B））存在显著关联。基因组最佳线性无偏预测（GCTA）分析发现，自我报告饮酒情况的基于SNP的遗传力为13%（标准误=0.01）。性别特异性分析发现，GWAS基因座在很大程度上重叠，男性和女性饮酒之间的遗传相关性（rG）为0.90（标准误=0.09，P值=7.16×10）。使用连锁不平衡评分回归分析发现，饮酒与受教育年限（rG=0.18，标准误=0.03）、高密度脂蛋白胆固醇（rG=0.28，标准误=0.05）、吸烟（rG=0.40，标准误=0.06）以及各种人体测量特征（例如超重，rG=-0.19，标准误=0.05）之间存在遗传重叠。这项研究重复了饮酒与酒精代谢基因以及KLB之间的关联，并确定了新的基因关联，这些关联应成为未来研究饮酒神经生物学的重点。
