Genetic epidemiology of complex diseases

复杂疾病的遗传流行病学

基本信息

批准号：
10025120
负责人：
Charles Rotimi
金额：
$ 338.7万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10025120
关键词：
Accounting Actins Adipose tissue Admixture Adult Africa Africa South of the Sahara African African American Americas Asthma Attention Bardet-Biedl Syndrome Biological CRISPR/Cas technology Cardiovascular Diseases Cell Count Cell Death Cells Childhood Chinese People Chromosome Mapping Clinical Clinical Research Communication Comorbidity Complex Country Custom Data Data Set Developed Countries Developing Countries Development Diabetes Mellitus Disease Disease susceptibility Drug Labeling Dyslipidemias Elephantiasis Embryo Environmental Risk Factor Ethiopia Ethnic group Etiology European Family Forensic Medicine Functional disorder Gene Frequency Genes Genetic Genetic Determinism Genetic Risk Genetic study Genome Genomic approach Genomics Genotype Ghana Glucose Goals Health Heart Diseases Hemoglobin Home environment Human Human Genetics Human Genome Hypertension Immigrant Immunologics Individual Inherited Insulin International Investigation Kenya Knock-out Knowledge Lead Leadership Life Style Light Linguistics Link Lipids Living Arrangement Malaria Metabolic Metabolic Diseases MicroRNAs Missense Mutation Mission Modeling Modernization Molecular Morbid Obesity Motor Multicenter Studies Mus Mutation Nature Nigeria Non-Insulin-Dependent Diabetes Mellitus Obesity Pain Paper Parents Pathogenesis Pathogenicity Pattern Pharmaceutical Preparations Phenotype Play Policies Population Population Heterogeneity Postdoctoral Fellow Predisposition Prevalence Study Property Proteins Proteomics Protocols documentation Publications Rare Diseases Recording of previous events Reporting Research Research Design Research Personnel Resources Role Sampling Science Scientist Serum Services Shotguns Sickle Cell Sickle Cell Anemia Site Smoking Staging Students Surveys System Training Training Programs Translating United States National Institutes of Health Unmarried person Variant Visceral Work Zebrafish analytical tool base boys clinical care database of Genotypes and Phenotypes design differential expression empowered epidemiologic data ethnic difference ethnic diversity follow-up genetic analysis genetic epidemiology genetic variant genome sciences genome wide association study genome-wide global health health disparity improved interest knock-down member mutant neglect novel novel strategies obesity genetics off-label drug programs recruit response risk variant screening sickling social tool trait transcriptome sequencing transcriptomics working group

项目摘要

Current activities within the Center for research on genomics and global health (CRGGH) builds on the more than two decades of research dedicated to investigating the pathogenesis of metabolic disorders, with attention to health disparities (HD). An overarching concern of CRGGH investigators is that health inequities between ethnic groups within the US and between developed and developing countries will widen if these populations are not fully involved in genomic science. Estimates of the proportion of genomic research conducted in diverse populations are discouraging, with over 90% of GWAS focusing on those of European descent. The notion that these findings will be broadly applicable to all global populations is flawed given findings of ethnic-specific risk variants and significant inter-ethnic differences in allele frequencies across the genome, as demonstrated by the wide variation in GWAS-associated variants across populations. We and others have demonstrated that genetic ancestry can be leveraged in the search for genetic risk variants and for improving clinical care. Thus, CRGGH investigators are committed to conducting original research in diverse ancestral populations, developing publicly-available international genomic resources and analytical tools to increase trans-ethnic gene mapping, and to train scientists from diverse ethnic backgrounds (see the mission statement at http://crggh.nih.gov/mission.cfm). As these goals are multi-faceted, we take advantage of a variety of strategies across the breadth of the research spectrum, incorporating new advances, such as integration of omics data and CRISPR/Cas9 technology, into the Centers work. We advanced our science by developing and participating in the development of several active protocols including: 1) H3Africa Multi-Centre Study of the Prevalence and Environmental and Genetic Determinants of T2D in Africa (11 sites in 8 countries to recruit 6,000 cases and 6,000 controls); 2) Investigation of the Pathogenesis of Podoconiosis using RNA-seq and immunologic approaches (Ethiopia); 3) Genetics of T2D in Diverse Populations (African ancestry individuals); 4) Genetics of T2D among Han Chinese; 5) Genetics of Obesity, Diabetes, and Heart Disease in African Diaspora Populations (AA and recent African immigrants); 6) Genomics, Environmental Factors and Social Determinants of Cardiovascular Disease in AA; 7) Active leadership and analyst roles in the multi-ethnic CHARGE Gene x Lifestyle Working Group; 8) Global Human Ancestry (5,966 genotyped individuals in 282 samples from global ethno-linguistic groups); 9) Advanced genetic analyses of dbGaP datasets for the study of complex traits; and 11) continued participation in the 1000 Genomes Project, which led to a Nature publication A global reference for human genetic variation55. 12) We continue to play a leadership role in the implementation of the H3Africa initiative, including the design of a custom chip array and our publication of the first H3Africa consortium paper, Enabling the genomic revolution in Africa in Science. 13) We are a member of the Consortium on Asthma among African ancestry Populations in the Americas (CAAPA) that developed the African Power Chip for the identification of risk variants for asthma and other complex traits. This work contributed to the development of the Multi-Ethnic Genotyping Array (MEGA). As part of CAAPA, we are conducting a clinical study of Asthma entitled New Approaches for Empowering Studies of Asthma in Populations of African Descent at the NIH clinical center in Bethesda, MD. Dyslipidemia: As part of the CHARGE Consortium, we lead the Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals that identified 13 new gene regions associated with serum lipids. Several of these novel discoveries were in African Americans emphasizing the need for more genomic studies different ancestral populations. Hypertension and related traits: a) In our African American project (HUFS), we showed that boys who grew up in two-parent homes are less likely to have elevated BP and HTN as adults compared to those raised by a single or neither parent. This is the first AA study to document an association between childhood family living arrangements and BP56. b) We contributed to the identification of novel variants (in EVX1-HOXA, RSPO3, and PLEKHG1) influencing BP and HTN susceptibility in AA57. Diabetes and related traits: a) We reported the largest genomic study of type 2 diabetes (T2D) in sub-Saharan Africans, having studied 5231 individuals from Nigeria, Ghana and Kenya. We identified known genomic variants and linked a novel gene ZRANB3 to the development of T2D (Nature Communications 2019). We used gene editing tools (CRISPR-Cas9 system) to knockout ZRANB3 in zebrafish, hence making the gene inoperative. We also created another zebrafish model where we used biological tools to reduce the expression of the ZRANB3 gene. In both cases, we observed a reduction in -cell numbers in the developing zebrafish embryo. Through further assessment, we realized it was because the -cells were being destroyed. To follow up on these results and identify the consequence of such -cell death, we took -cell cells from mice and performed a similar knockdown of the ZRANB3 gene as in the zebrafish model. We found that cells with ZRANB3 knockdown released much less insulin in the presence of high glucose than normal mice -cells. We also used transcriptomics of visceral adipose tissue from AA to profile differentially-expressed genes in T2D associated with morbid obesity. We detected 68 differentially expressed genes, including MYO10, which encodes an actin-based motor protein that has been associated with T2D. Our upstream regulator analysis predicted five miRNAs as regulators of the expression changes. d) We used shotgun proteomics to dissect the molecular mechanism underlying the metabolically healthy but obese (MHO) phenotype (obese people without comorbidities like diabetes, dyslipidemia or hypertension) in contrast to the metabolically abnormal obese phenotype (MAO). Genomics of neglected and rare diseases: Our 2012 NEJM publication shed light on the genetic basis of podoconiosis, a neglected tropical endemic non-filarial elephantiasis, and our research also led to the clinical staging of the disease. We discovered two novel missense mutations in BBS5 with pathogenic properties and implications for screening for Bardet-Biedl syndrome in Africans. We were lead authors on the first publication of the AGVP, which found novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa and demonstrated improved imputation accuracy and presented an efficient genotype array design for GWAS in Africans. -Saharan Africa". We investigated ancestry of 3,528 modern humans from 163 global samples and identified 19 ancestral components, with 94.4% of individuals showing mixed ancestry; the ubiquity of mixed ancestry underscores the importance of accounting for ancestry in history, forensics, health, and drug labeling. Lastly, our recent research into the origin of the sickle mutation attracted international interests. Briefly, inheriting two copies of a hemoglobin gene carrying the sickle mutation leads to a painful condition called sickle cell disease, which historically was fatal during childhood. However, inheriting only one copy of the mutant hemoglobin gene leads to protection against malaria, which kills 400,000 people each year. By surveying the genomes of 2,932 people from around the world, we found that 156 individuals who carried one copy of the sickle cell mutation inherited the same mutation from a single person who lived approximately 7,300 years ago. We also identified 27 other mutations that tend to be inherited with the sickle mutation. One or more of these other mutations ma

关于基因组学和全球健康研究中心（CRGGH）的当前活动基于致力于研究代谢疾病发病机理的二十年研究，并关注健康差异（HD）。 CRGGH调查人员的总体关注点是，如果这些人群不完全参与基因组科学，美国境内以及发达国家和发展中国家之间的健康不平等将扩大。在不同人群中进行的基因组研究比例的估计令人信服，超过90％的GWA专注于欧洲血统的GWA。考虑到种族特异性风险变异的发现以及整个基因组等位基因频率的明显种族间差异的发现，这些发现将广泛适用于所有全球人群，这是有缺陷的，这表明，GWAS相关变体的广泛变化证明了这一群体的频率。我们和其他人已经证明，可以利用遗传血统来寻找遗传风险变异并改善临床护理。因此，CRGGH研究人员致力于对不同祖先人群进行原始研究，开发公共可用的国际基因组资源和分析工具，以增加跨种族基因地图，并培训来自不同种族背景的科学家（请参阅http:////crggh.nih.gov/simply.cfm）。由于这些目标是多方面的，因此我们利用了整个研究范围的各种策略，将新进步（例如OMICS数据和CRISPR/CAS9技术集成）纳入中心的工作。我们通过制定和参与制定多种有效协议的制定，包括：1）非洲T2D的患病率，环境和遗传决定因素（8个国家的11个地点，招募6,000例和6,000例控制的11个地点）的H3AFRICA多中心研究； 2）使用RNA-Seq和免疫方法（埃塞俄比亚）研究畸形病的发病机理； 3）T2D的遗传学（非洲血统个体）； 4）汉族中国t2d的遗传学； 5）非洲侨民种群中肥胖，糖尿病和心脏病的遗传学（AA和最近的非洲移民）； 6）AA中心血管疾病的基因组，环境因素和社会决定因素； 7）在多种族指控基因X生活方式工作组中的积极领导和分析师角色； 8）全球人类血统（来自全球民族语言群体的282个样本中的5,966个基因分型个体）； 9）用于研究复杂性状的DBGAP数据集的高级遗传分析； 11）继续参与1000个基因组项目，这导致自然出版物成为人类遗传变异的全球参考55。 12）我们继续在实施H3africa倡议的实施中发挥领导作用，包括设计定制芯片阵列以及我们出版了第一本H3africa财团论文，从而使科学的基因组革命成为了科学的基因组革命。 13）我们是美洲（CAAPA）中非洲血统人群中哮喘联盟的成员，该群体开发了非洲权力芯片，以识别哮喘和其他复杂性状的风险变异。这项工作有助于多种族基因分型阵列（Mega）的发展。作为CAAPA的一部分，我们正在对马里兰州贝塞斯达NIH临床中心的非洲血统哮喘研究的哮喘进行临床研究。血脂异常：作为电荷联盟的一部分，我们领导了387,272个个体的多熟悉基因组吸烟研究研究，这些研究鉴定了13个与血清脂质相关的新基因区域。其中一些新颖的发现是在非裔美国人中强调了对不同祖先种群的更多基因组研究的需求。高血压和相关特征：a）在我们的非裔美国人项目（HUFS）中，我们表明，与单个父母或两家父母所抚养的男孩相比，在两父母住宅中长大的男孩的BP和HTN的可能性较小。这是第一次记录童年家庭生活安排与BP56之间关联的AA研究。 b）我们有助于鉴定新型变体（在EVX1-HOXA，RSPO3和PLEKHG1中）影响AA57中BP和HTN敏感性。糖尿病和相关特征：a）我们报告了撒哈拉以南非洲人的2型糖尿病（T2D）最大的基因组研究，研究了来自尼日利亚，加纳和肯尼亚的5231个人。我们确定了已知的基因组变体，并将一种新颖的基因Zranb3与T2D的开发联系起来（自然通信2019）。我们使用基因编辑工具（CRISPR-CAS9系统）在斑马鱼中敲除Zranb3，因此使该基因不起作用。我们还创建了另一个斑马鱼模型，在该模型中我们使用生物学工具来减少Zranb3基因的表达。在这两种情况下，我们都观察到发育中的斑马鱼胚胎中细胞数量的减少。通过进一步的评估，我们意识到这是因为 - 细胞被摧毁。为了跟进这些结果并确定这种细胞死亡的结果，我们从小鼠中取了细胞，并对Zranb3基因进行了类似的敲低，与斑马鱼模型中一样。我们发现，Zranb3敲低的细胞在存在高葡萄糖的情况下释放的胰岛素要比正常小鼠细胞少得多。我们还使用了从AA的内脏脂肪组织的转录组学到与病态肥胖相关的T2D差异表达的基因。我们检测到68个差异表达的基因，包括MyO10，该基因编码与T2D相关的基于肌动蛋白的运动蛋白。我们的上游调节剂分析预测五个miRNA是表达变化的调节剂。 d）我们使用shot弹枪蛋白质组学来剖析代谢健康但肥胖（MHO）表型的分子机制（与代谢异常异常的肥胖型（MAO）相反，我们的表型（MHO）表型（肥胖的人，例如糖尿病，血脂异常或高血压）。被忽视和罕见疾病的基因组学：我们的2012年NEJM出版物阐明了遗传学基础，一种被忽视的热带特有非依恋性非抗原病的遗传基础，我们的研究也导致了疾病的临床阶段。我们在BBS5中发现了两个新型的错义突变，具有致病性能，以及对非洲人中Bardet-Biedl综合征筛查的影响。我们是AGVP首次出版的首席作者，该出版物在撒哈拉以南非洲地区发现了复杂，区域截然不同的猎人 - 采集者和欧亚混合的新证据，并显示出提高的插补准确性，并为非洲人的GWAS提供了有效的基因型阵列设计。 - 萨哈拉非洲。遗传携带镰刀突变的血红蛋白基因的两个副本会导致一种称为镰状细胞疾病的痛苦，在童年时期，这是致命的。从大约7300年前生活的一个人那里继承了相同的突变。这些其他突变中的一个或多个