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

与非酒精性脂肪肝相关基因座的鉴定和表征

• 批准号: 10372217
• 负责人: Nicholette D. Allred
• 金额: $ 68.86万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372217
• 关键词: Affect; African; African ancestry; Alleles; Biological; CRISPR screen; CRISPR/Cas technology; Cell Line; Cells; Data; Diagnosis; Disease; Ethnic Origin; Ethnic group; Etiology; European; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Gene Frequency; Genes; Genetic; Genomics; Glycogen; Goals; Hepatocyte; Heritability; High Prevalence; Hispanic Populations; Hispanic ancestry; Histologic; Histology; Human; Image; Individual; Investments; Knock-out; Link; Liver; Liver diseases; Measures; Medical; Meta-Analysis; Minority Groups; National Heart, Lung, and Blood Institute; Obesity associated liver disease; Pathology; Population; Population Heterogeneity; Predisposition; Prevalence; Prevention; Public Health; Publishing; Resources; Risk; Role; Signal Transduction; Testing; Therapeutic Intervention; Time; Trans-Omics for Precision Medicine; United States National Institutes of Health; Variant; Weight; Work; X-Ray Computed Tomography; attenuation; base; causal variant; chronic liver disease; clinical practice; cohort; cost; ethnic diversity; follow-up; genetic architecture; genome sequencing; genome wide association study; genome wide screen; genome-wide; genomic locus; improved; insight; loss of function; minimal risk; multi-ethnic; non-alcoholic fatty liver disease; novel; obesity genetics; population based; prevent; rare variant; targeted treatment; whole genome

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.

项目概要 非酒精性脂肪肝病 (NAFLD) 是由肝脏中脂肪过度积累（脂肪变性）引起的，全球患病率为 25.2%，是全球慢性肝病的最常见原因。预防或治疗 NAFLD 的有效方法很少，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进诊断和治疗。 NAFLD 是一种高度遗传性疾病 (20-70%)，其患病率因种族而异，即西班牙裔个体的患病率高于欧洲和非洲裔个体。第一个发表的 GWAS 是我们来自肥胖相关肝病遗传学 (GOLD) 联盟的工作，确定了欧洲血统人群中与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，并确定了祖先特定等位基因，表明少数群体中可能存在新的疾病促进基因座。由于已知的变异只能解释肝脏衰减变异的 4.8%，因此影响 NAFLD 易感性的其他基因位点仍有待发现。此应用程序的目的是通过全基因组测序 (WGS) 在 NHLBI 精准医学跨组学 (TOPMed) 联盟 (n=23,156) 中的不同种族人群中识别对 NAFLD 产生影响的其他罕见变异。我们将通过将 GWAS 数据归入 TOPMed 参考组，在缺乏 WGS 的 GOLD 队列 (n=8,865) 中复制效果。这些单一罕见变异和罕见变异负荷测试分析中涉及的基因将进行功能测试，以了解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变异会导致变异和风险。这些全基因组测序确定的变异可以帮助优先考虑可用于 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，并将这些关联与可作为治疗干预目标的基因联系起来。