Genetic risk factors for alcoholic cirrhosis - genome-wide case-control study

酒精性肝硬化（ALC）在世界范围内引起显著死亡。世界卫生组织2014年 《酒精与健康》报告称，全球50%的肝硬化死亡率是由酒精引起的， 在北美和欧洲高达约60%。原则上，所有酒精性肝病都是可以预防的， 适当的行为和生活方式改变，包括药物治疗。然而， 由于对这两方面的认识不足， 遗传和非遗传因素对这种疾病的发病机制作出贡献。整体 目标是确定在人类中发生ALC的潜在遗传风险的基因座、基因和多态性， 酗酒者为了做到这一点，多国基因组ALC联盟已经成功地收集了广泛的 表型数据和血液/DNA来自>5000名重度饮酒者，有和没有肝硬化， 2016-2017年通过全基因组SNP关联方法进行基因分型（UO 1-AA 018389）。 通过其他重要的合作，该联盟获得了额外的约2000个基因型- 表型数据使其成为ALC遗传学最大的发现队列。该财团还做了 识别和访问“大型队列”基因组生物库（如英国生物库）的基础， 独立验证队列。 本申请的具体目的是，目的1：通过以下方法鉴定ALC的遗传风险因素： GenomALC发现队列中的病例对照GWAS（n=~7411）;目的2：确认 从已建立的“大型队列”基因组数据库中获得独立的验证队列;目标3： 对酒精性肝硬化的其他GWAS结果进行荟萃分析;目的4：检查 酒精性肝硬化与潜在相关疾病和肝硬化生物标志物之间的遗传风险。 GenomALC团队（遗传学家，遗传统计学家，临床医生）拥有正确的专业知识，技能和 建立基础设施来进行这些分析。这种大型病例对照GWAS具有以下能力： 识别新SNPs，创造新知识并推断导致酒精性肝硬化的途径/机制， 从而识别新的或重新利用的药物治疗的潜在靶点。

Alcoholic liver cirrhosis (ALC) causes a significant mortality worldwide. World Health Organization 2014 Report on ‘alcohol and health’ reports 50% of liver cirrhosis mortality worldwide is due to alcohol, reaching as high as ~60% in north America and Europe. In principle, all alcoholic liver diseases are preventable with appropriate behavioral and lifestyle change, including pharmaceutical approaches. However, progress in developing specific pharmaceutical interventions has been hampered by poor understanding of both genetic and non-genetic factors contributing towards the pathogenesis of this disease. The OVERALL GOAL is to identify loci, genes and polymorphisms underlying genetic risk for the development of ALC in heavy drinkers. To do this the multinational GenomALC Consortium has successfully collected extensive phenotype data and blood/DNAs from >5000 heavy drinkers with and without cirrhosis which will be subjected to genotyping via genome-wide SNP association approach in 2016-2017 (UO1-AA018389). Through other significant collaborations, the consortium has access to additional ~2000 genotype- phenotype data making it the largest discovery cohort for ALC genetics. The consortium has also done the groundwork in identifying and accessing ‘mega-cohort’ Genomics Biobanks (e.g UK Biobank) as independent validation cohorts. The specific aims of the current application are, aim 1: To identify genetic risk factors for ALC through case-control GWAS in GenomALC discovery cohort (n=~7411); aim 2: To confirm allelic associations in independent validation cohorts available from established ‘mega-cohort’ genomic databases; aim 3: To perform meta-analysis with results from other GWAS on alcoholic cirrhosis; aim 4: To examine overlap in genetic risk between alcoholic cirrhosis and potentially related diseases and biomarkers of cirrhosis. The GenomALC team (geneticists, genetic statisticians, clinicians) has the right expertise, skills and established infrastructure to perform these analyses. This large case-control GWAS has the power to identify novel SNPs, create new knowledge and infer pathways/mechanisms leading to alcoholic cirrhosis, thus identifying potential targets for new or repurposed drug treatments.