Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease

非酒精性脂肪性肝病的综合多基因遗传学研究 摘要 非酒精性脂肪性肝病(NAFLD)是由肝脏脂肪变性(脂肪堆积)引起的， 在美国，多达2900万成年人受到影响，已成为肝病的主要原因。 非酒精性脂肪肝可导致肝硬变和肝细胞癌。几乎没有有效的方法来 预防或治疗非酒精性脂肪肝。需要对NAFLD的病因学有更好的了解，以改善其 诊断和治疗。非酒精性脂肪肝是可遗传的(受基因影响)，并被认为是常见的 解释这一性状约20%遗传力的变异，表明更多的因果变异 影响这一性状还有待发现。虽然组织学在历史上被用来定义 NAFLD脂肪变性，NAFLD现在常规诊断为非侵入性成像或升高 ALT/AST，无其他肝病。我们最近出版了世界上最大的 我们鉴定了&gt；300的血清ALT/AST/ALP的交叉血统分析 与这些特征相关的全基因组显著变异；其中23个也与 使用肝脏成像评估了7600人中肝脏脂肪变性的增加。我们展示了 来自ALT而不是AST或ALP全基因组的多基因风险评分(PRS)具有显著意义 变异能够预测脂肪变性、肝硬变和肝细胞癌。在这里，我们聚集了世界上最大的 用肝脏成像或NAFLD测量肝脏脂肪变性的多民族样本收集 根据疾病代码的国际分类进行诊断，并提供全基因组数据。 我们假设(1)常见的和低频的变异对NAFLD的变异和 风险(2)总体上识别的变异将改善对肝脏脂肪变性、肝硬变的风险预测 和肝细胞癌相比，(3)GWASNAFLD优先基因，当靶向时， 会在肝细胞中自主发挥作用，导致脂肪变性。此应用程序的目标是 对影像或ICD诊断为NAFLD的NAFLD进行GWASMeta分析。A RPS 将从经过验证的NAFLD相关变体效果中创建并评估其能力 预测，脂肪变性，肝硬变，肝癌。我们将对经过验证的NAFLD关联变体进行注释 确定用于后续功能研究的靶基因，以单独和联合应用于脂肪变性 组合。这项工作的结果将有助于定义遗传和代谢机制， 引起NAFLD并为开发新的生物标记物以及潜在的治疗方法提供信息 这种情况。

Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease Summary Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis (lipid accumulation), affects up to 29 million adults in the U.S. and has become the leading cause of liver disease. NAFLD can lead to liver cirrhosis and hepatocellular carcinoma. There are few effective ways to prevent or treat NAFLD. A better understanding of NAFLD etiology is needed to improve its diagnosis and treatment. NAFLD is heritable (genetically influenced) and identified common variants that explain ~20% of heritability of this trait, suggesting that more causal variants that affect this trait remain to be discovered. While histology has historically been used to define NAFLD steatosis, NAFLD is now routinely diagnosed using non invasive imaging or elevated ALT/AST without the presence of other liver diseases. We recently published the world’s largest cross ancestry GWAS analysis of serum ALT/AST/ALP GWAS where we identified >300 genome wide significant variants that associate with these traits; 23 of them also associated with increased hepatic steatosis assessed in 7600 individuals using liver imaging. We showed that a polygenic risk score (PRS) from the ALT but not AST or ALP genome wide significant variants was able to predict steatosis, cirrhosis, and HCC. Here, we have assembled the largest collection of multiethnic samples with hepatic steatosis measured with liver imaging or NAFLD diagnosed by international classification of disease code with genome wide data also available. We hypothesize that (1) common and low frequency variants contribute to NAFLD variation and risk (2) identified variants in aggregate will improve risk prediction for liver steatosis, cirrhosis and HCC compared to single variants and (3) GWAS NAFLD prioritized genes, when targeted, will function autonomously in hepatocytes to cause steatosis. The objective of this application is to carry out a GWAS meta analysis of NAFLD across imaging or ICD diagnosed NAFLD. A PRS will be created from verified NAFLD associated variants effect and assessed for its ability to predict, steatosis, cirrhosis, HCC. We will annotate verified NAFLD associated variants to identify target genes for follow up functional studies for effects on steatosis alone and in combination. Results from this work will help define the genetic and metabolic mechanisms that cause NAFLD and inform development of new biomarkers as well as potential therapeutics for this condition.