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

基因组学和全球健康研究中心 (CRGGH) 目前的活动建立在二十多年来致力于调查代谢紊乱发病机制的研究基础上，并关注健康差异 (HD)。 CRGGH 研究人员最关心的问题是，如果美国境内的族群之间以及发达国家和发展中国家之间的健康不平等现象将会扩大，如果这些人群没有充分参与基因组科学的话。对不同人群中进行的基因组研究比例的估计令人沮丧，超过 90% 的 GWAS 重点关注欧洲血统的人群。鉴于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显着种族间差异，这些发现将广泛适用于全球所有人群的观点是有缺陷的，正如不同人群中 GWAS 相关变异的巨大差异所证明的那样。我们和其他人已经证明，遗传血统可以用于寻找遗传风险变异和改善临床护理。因此，CRGGH 的研究人员致力于在不同的祖先人群中进行原创性研究，开发公开可用的国际基因组资源和分析工具，以增加跨种族基因图谱，并培训来自不同种族背景的科学家（参见使命声明：http:// /crggh.nih.gov/mission.cfm）。由于这些目标是多方面的，我们利用整个研究领域的各种策略，将新的进展（例如组学数据和 CRISPR/Cas9 技术的集成）融入到中心的工作中。我们通过制定和参与制定多项活跃协议来推进我们的科学发展，其中包括：1) H3Africa 非洲 T2D 患病率、环境和遗传决定因素的多中心研究（8 个国家的 11 个地点，招募 6,000 例病例和 6,000 例对照） ; 2) 使用 RNA-seq 和免疫学方法研究脚足病的发病机制（埃塞俄比亚）； 3) 不同人群（非洲血统个体）中 T2D 的遗传学； 4）汉族2型糖尿病的遗传学； 5) 非洲侨民（AA 和最近的非洲移民）肥胖、糖尿病和心脏病的遗传学； 6) AA 心血管疾病的基因组学、环境因素和社会决定因素； 7) 在多种族 CHARGE Gene x Lifestyle 工作组中担任积极的领导和分析师角色； 8) 全球人类祖先（来自全球民族语言群体的 282 个样本中的 5,966 个个体进行基因分型）； 9) dbGaP 数据集的高级遗传分析，用于研究复杂性状； 11) 继续参与千人基因组计划，该计划导致《自然》杂志发表《人类遗传变异的全球参考》55。 12) 我们继续在 H3Africa 计划的实施中发挥领导作用，包括设计定制芯片阵列以及我们发表第一篇 H3Africa 联盟论文《实现非洲科学中的基因组革命》。 13) 我们是美洲非洲裔哮喘联盟 (CAAPA) 的成员，该联盟开发了非洲功率芯片，用于识别哮喘和其他复杂特征的风险变异。这项工作促进了多种族基因分型阵列 (MEGA) 的开发。作为 CAAPA 的一部分，我们正在马里兰州贝塞斯达的 NIH 临床中心开展一项名为“非洲裔人群哮喘研究新方法”的哮喘临床研究。血脂异常：作为 CHARGE 联盟的一部分，我们领导了针对 387,272 名个体的多祖先全基因组基因吸烟相互作用研究，确定了 13 个与血脂相关的新基因区域。其中一些新发现来自非裔美国人，强调需要对不同祖先群体进行更多基因组研究。高血压和相关特征：a) 在我们的非裔美国人项目 (HUFS) 中，我们发现，与单亲家庭或非父母家庭抚养的男孩相比，在双亲家庭长大的男孩成年后血压和高血压的可能性较小。这是第一个记录童年家庭生活安排与 BP56 之间关联的 AA 研究。 b) 我们帮助鉴定了影响 AA57 中血压和高血压易感性的新变异（EVX1-HOXA、RSPO3 和 PLEKHG1）。糖尿病和相关特征：a) 我们报告了撒哈拉以南非洲地区最大规模的 2 型糖尿病 (T2D) 基因组研究，研究了来自尼日利亚、加纳和肯尼亚的 5231 名个体。我们鉴定了已知的基因组变异，并将新基因 ZRANB3 与 T2D 的发展联系起来（Nature Communications 2019）。我们使用基因编辑工具（CRISPR-Cas9系统）敲除斑马鱼中的ZRANB3，从而使该基因失效。我们还创建了另一个斑马鱼模型，在其中使用生物工具来减少 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的细胞数量减少。通过进一步的评估，我们意识到这是因为细胞被破坏了。为了跟踪这些结果并确定此类细胞死亡的后果，我们从小鼠身上取出了细胞，并像斑马鱼模型中那样对 ZRANB3 基因进行了类似的敲低。我们发现，在高葡萄糖存在下，ZRANB3 敲低的细胞释放的胰岛素比正常小鼠细胞少得多。我们还使用 AA 内脏脂肪组织的转录组学来分析与病态肥胖相关的 T2D 中差异表达的基因。我们检测到 68 个差异表达基因，包括 MYO10，它编码与 T2D 相关的基于肌动蛋白的运动蛋白。我们的上游调节因子分析预测了五种 miRNA 作为表达变化的调节因子。 d) 我们使用鸟枪法蛋白质组学来剖析代谢健康但肥胖 (MHO) 表型（没有糖尿病、血脂异常或高血压等合并症的肥胖人群）与代谢异常肥胖表型 (MAO) 之间的分子机制。被忽视和罕见疾病的基因组学：我们 2012 年《NEJM》出版物揭示了脚足病（一种被忽视的热带地方性非丝虫象皮病）的遗传基础，我们的研究还导致了该疾病的临床分期。我们在 BBS5 中发现了两种新的错义突变，具有致病特性，对非洲人 Bardet-Biedl 综合征筛查具有重要意义。我们是 AGVP 第一份出版物的主要作者，该出版物发现了撒哈拉以南非洲地区复杂的、区域性独特的狩猎采集者和欧亚混血的新证据，并证明了估算准确性的提高，并为非洲人的 GWAS 提供了有效的基因型阵列设计。 -撒哈拉非洲”。我们从 163 个全球样本中调查了 3,528 名现代人类的血统，并确定了 19 个祖先成分，其中 94.4% 的个体表现出混合血统；混合血统的普遍性强调了在历史、法医、健康、最后，我们最近对镰状突变起源的研究引起了国际关注，简单地说，继承了两个方面。携带镰状突变的血红蛋白基因的副本会导致一种称为镰状细胞病的痛苦疾病，这种疾病在儿童时期是致命的。然而，仅继承突变血红蛋白基因的一个副本就可以预防疟疾，疟疾每年导致 40 万人死亡。通过调查来自世界各地的 2,932 人的基因组，我们发现 156 名携带镰状细胞突变副本的人从一个生活在大约7,300 年前，我们还发现了其他 27 种可能与镰状突变一起遗传的突变。这些其他突变中的一种或多种可能