Identification and Characterization of Loci Associated with Non-alcoholic Fatty Liver Disease

项目摘要 非酒精性脂肪性肝病（NAFLD）由肝脏中脂肪的过度积累（脂肪变性）引起，全球患病率为25.2%，是全球慢性肝病最常见的原因。几乎没有有效的方法来预防或治疗NAFLD，使其成为我们这个时代最大的未满足的公共卫生需求之一。需要更好地了解病理生理学，以改善诊断和治疗。NAFLD是一种高度遗传性疾病（20-70%），其患病率在不同种族群体中存在差异，即西班牙裔个体的患病率高于欧洲和非洲裔个体。最早发表的GWAS之一是我们来自肥胖相关肝病遗传学（GOLD）联盟的工作，确定了与欧洲血统人群中计算机断层扫描测量的肝脏衰减相关的五个位点。跨种族分析证实了一些关联，并确定了祖先特异性等位基因，表明少数民族人群中可能存在新的疾病促进基因座。由于已知的变异仅解释了肝脏衰减的4.8%的变异，因此影响NAFLD易感性的其他遗传位点仍有待发现。本申请的目的是通过全基因组测序（WGS）在NHLBI的精准医学（TOPMed）联盟（n= 23，156）中包含的种族多样性人群中鉴定对NAFLD有影响的其他罕见变异。我们将通过将GWAS数据插补到TOPM参考组中，在缺乏WGS的GOLD队列（n= 8，865）中复制效应。将对这些单一罕见变异体和罕见变异体负荷检测分析中的相关基因进行功能性检测，以确定其对肝脂肪变性的影响，以确认因果关系。我们的中心假设是，罕见的变异有助于变异和风险。这些WGS鉴定的变体可以帮助优先考虑可以靶向NAFLD治疗的基因座。我们的长期目标是通过了解基因组对病理生理学的贡献来改善NAFLD的诊断、管理、治疗和最终预防。我们的工作结果将帮助我们了解NAFLD的遗传结构，并将这些关联与可用于治疗干预的基因联系起来。

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD), caused by excess accumulation of fat in the liver (steatosis), has a global prevalence of 25.2% and is the most common cause of chronic liver disease worldwide. There are few effective ways to prevent or treat NAFLD making it one of the biggest unmet public health needs of our time. A better understanding of the pathophysiology is needed to improve diagnosis and treatment. NAFLD is a highly heritable disease (20-70%) with prevalence rates that vary across ethnic groups, i.e. individuals of Hispanic ancestry have a higher prevalence than European and African ancestry individuals. One of the first published GWAS was our work from the Genetics of Obesity-associated Liver Disease (GOLD) Consortium identifying five loci associated with computed tomography-measured liver attenuation in European-ancestry populations. Trans ethnic analyses confirmed some associations and also identified ancestry specific alleles suggesting novel disease promoting loci may exist in minority populations. Since known variation explains only 4.8% of the variance in liver attenuation, additional genetic loci that impact predisposition to NAFLD remain to be discovered. The objective of this application is to identify additional rare variants with effects on NAFLD through whole genome sequencing (WGS) in ethnically diverse populations included in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) Consortium (n=23,156). We will replicate effects in GOLD cohorts (n=8,865) lacking WGS by imputing GWAS data to the TOPMed reference panel. Implicated genes from these single rare variant and rare variant burden testing analyses will be functionally tested for effects on hepatic steatosis to confirm causality. Our central hypothesis is that rare variants contribute to variation and risk. These WGS identified variants can help prioritize loci that can be targeted for NAFLD therapy. Our long-term goal is to improve the diagnosis, management, treatment and ultimately prevention of NAFLD by understanding the genomic contributions to pathophysiology. Results from our work will help us to understand the genetic architecture of NAFLD and link these associations to genes that can be targeted for therapeutic intervention.