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

基本信息

批准号：
10597023
负责人：
Nicholette D. Allred
金额：
$ 66.4万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10597023
关键词：
Affect African African ancestry Alleles Biological CRISPR screen CRISPR/Cas technology Cell Line Cells Data Diagnosis Disease Ethnic Origin Ethnic Population Etiology European European ancestry 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 Maps 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 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 genome-wide analysis 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

项目摘要

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 (NAFLD) 是由肝脏中脂肪过多堆积（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，目前几乎没有有效的方法来预防或预防。 NAFLD 是一种高度遗传性疾病（20-70%），其患病率很高，因此需要更好地了解其病理生理学。不同种族群体的发病率有所不同，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 工作是我们来自肥胖相关肝病遗传学 (GOLD) 联盟的工作，确定了与肥胖相关的五个位点。计算机断层扫描测量的欧洲血统人群的肝脏衰减分析证实了一些关联，并确定了血统特异性等位基因，表明少数群体中可能存在新的疾病促进基因座。由于已知变异仅解释了肝脏衰减变异的 4.8%，因此影响 NAFLD 易感性的其他基因位点仍有待发现。本应用的目的是通过全基因组测序 (WGS) 识别对 NAFLD 产生影响的其他罕见变异。 NHLBI 精准医学跨组学 (TOPMed) 联盟中包含的种族多样化人群 (n=23,156) 我们将在 GOLD 队列中复制效果。 (n=8,865) 缺乏 WGS，通过将 GWAS 数据归入 TOPMed 参考组，将对这些单一罕见变异和罕见变异负荷测试分析中的相关基因进行功能测试，以验证其对肝脂肪变性的影响，以确认罕见变异之间的因果关系。这些 WGS 识别的变异可以帮助确定 NAFLD 治疗的目标位点，我们的长期目标是通过了解 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。