Genetic epidemiology of complex diseases

复杂疾病的遗传流行病学

• 批准号: 9571144
• 负责人: Charles Rotimi
• 金额: $ 314.21万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 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/9571144
• 关键词: Accounting; Actins; Adipose tissue; Admixture; Adult; Affect; Africa; Africa South of the Sahara; African; African American; Alleles; Americas; Asthma; Attention; Bardet-Biedl Syndrome; Biological; CRISPR/Cas technology; Candidate Disease Gene; Cardiovascular Diseases; Childhood; Chinese People; Chromosome Mapping; Clinical; Collagen; Comorbidity; Complex; Country; Custom; Data; Data Aggregation; Data Set; Developing Countries; Development; Diabetes Mellitus; Diet; Disease; Disease susceptibility; Drug Labeling; Dyslipidemias; Elephantiasis; Enhancers; Environmental Risk Factor; Ethiopia; Ethnic group; Etiology; European; Family; Fetal Hemoglobin; Forensic Medicine; Functional disorder; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Risk; Genetic study; Genome; Genomic approach; Genomics; Genotype; Globin; Goals; HLA-B Antigens; Haplotypes; Health; Heart Diseases; Hemoglobin; Hemolysis; Home environment; Human; Human Genetics; Human Genome; Hypertension; Hyperuricemia; IGF2 gene; Immigrant; Immunologics; Individual; International; Investigation; Knowledge; Lead; Leadership; Life Style; Light; Linguistics; Lipids; Living Arrangement; Malaria; Meta-Analysis; Metabolic; Metabolic Diseases; MicroRNAs; Missense Mutation; Mission; Modeling; Modernization; Molecular; Morbid Obesity; Motor; Multicenter Studies; Myoclonic Epilepsies; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Osteogenesis Imperfecta; 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; Recruitment Activity; Reporter Genes; Reporting; Research; Research Personnel; Resources; Risk; Role; Sampling; Science; Scientist; Serum; Services; Shotguns; Sickle Hemoglobin; Site; South Africa; Staging; Statistical Data Interpretation; Students; Technology; Training; Training Programs; Translating; United States National Institutes of Health; Uric Acid; Variant; Visceral; Work; analytical tool; base; boys; clinical care; cyclophilin B; database of Genotypes and Phenotypes; design; differential expression; epidemiologic data; ethnic difference; ethnic diversity; exome; founder mutation; genetic analysis; genetic epidemiology; genome wide association study; genome-wide; global health; health disparity; improved; member; neglect; novel; programs; response; risk variant; screening; social; trait; transcriptome sequencing; transcriptomics; working group

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 particular 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 fully 96% of GWAS focusing on those of European descent2. 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) Genetic Study of Myoclonic Epilepsy (whole exomes and genotyping of affected families from South Africa); 8) Active leadership and analyst roles in the multi-ethnic CHARGE Gene x Lifestyle Working Group, which has aggregated data on over 130,000 individuals, including almost 24,000 AA; 9) Global Human Ancestry (5,966 genotyped individuals in 282 samples from global ethno-linguistic groups); 10) 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). Dyslipidemia: We sequenced lipid candidate genes in AA with extreme lipid profiles and genotyped the observed variation in a larger sample of AA. Notable among our findings were local ancestry-specific genetic effects at the LPL locus. Among AA with no African ancestry alleles for LPL variant rs328, the association between this variant and lipids was what has been previously observed among European Ancestry individuals, while among AA with 2 African ancestry alleles, the association was much smaller, similar to what was observed among West Africans, despite vastly different lifestyles and diets between AA and West Africans. 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. c) We discovered an association of the -globin locus with serum uric acid levels in admixed AA. At rs2855126, the ancestral allele is associated with higher levels of serum uric acid and higher levels of reporter gene expression. We hypothesize that enhancer activity associated with the ancestral allele drives higher expression of -globin, leading to increased levels of fetal hemoglobin and conferring protection against malaria independent of hemoglobin S. We also hypothesize that higher expression of -globin leads to hemoglobin imbalance, in turn leading to increased hemolysis and higher levels of serum uric acid. Subsequently, higher levels of serum uric acid are associated with increased risk of hyperuricemia and hypertension. Diabetes and related traits: a) In our African diabetes project (AADM), we completed the first large-scale replication and fine mapping analysis of reported T2D-associated risk loci in Africans. Of 106 reported T2D GWAS loci, 41 showed transferability to our African sample and most of the 41 loci were localized to smaller haplotypes than in the original reports. Our lab provided leadership and statistical analysis for the largest (n>23,000) meta-analysis of the AA diabetes consortium (MEDIA). We identified two novel loci (HLA-B and INS-IGF2) that were genome-wide significant. c) We 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 identified a founder mutation in LEPRE1 that causes lethal recessive osteogenesis imperfecta (OI) in AA and West Africans; reported a lack of cyclophilin B in OI with normal collagen folding; and 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.

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，特别关注健康差异 (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，96% 的 GWAS 都集中在欧洲血统2。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) 肌阵挛性癫痫的遗传学研究（来自南非受影响家庭的全外显子组和基因分型）； 8) 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，该工作组汇总了超过 130,000 人的数据，其中包括近 24,000 名 AA； 9) 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）； 10) 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。血脂异常：我们对具有极端脂质谱的 AA 中的脂质候选基因进行了测序，并对更大的 AA 样本中观察到的变异进行了基因分型。我们的发现中值得注意的是 LPL 基因座的当地血统特异性遗传效应。在没有 LPL 变体 rs328 的非洲血统等位基因的 AA 中，该变体与脂质之间的关联与之前在欧洲血统个体中观察到的情况相同，而在具有 2 个非洲血统等位基因的 AA 中，这种关联要小得多，与观察到的情况相似尽管 AA 和西非人的生活方式和饮食截然不同，但西非人之间的差异却很大。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）。 c) 我们发现混合 AA 中 β 珠蛋白基因座与血清尿酸水平存在关联。在 rs2855126，祖先等位基因与较高水平的血清尿酸和较高水平的报告基因表达相关。我们假设与祖先等位基因相关的增强子活性驱动更高的β珠蛋白表达，导致胎儿血红蛋白水平增加，并提供独立于血红蛋白S的抗疟疾保护。我们还假设更高的β珠蛋白表达反过来会导致血红蛋白失衡导致溶血增加和血清尿酸水平升高。随后，较高水平的血清尿酸与高尿酸血症和高血压的风险增加相关。糖尿病和相关特征：a) 在我们的非洲糖尿病项目 (AADM) 中，我们完成了对非洲人报告的 T2D 相关风险位点的首次大规模复制和精细定位分析。在 106 个报告的 T2D GWAS 位点中，有 41 个显示出可转移到我们的非洲样本，并且 41 个位点中的大多数定位于比原始报告中更小的单倍型。我们的实验室为 AA 糖尿病联盟 (MEDIA) 最大的 (n>23,000) 荟萃分析提供领导和统计分析。我们鉴定了两个在全基因组范围内具有重要意义的新位点（HLA-B 和 INS-IGF2）。 c) 我们使用 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。我们发现了 LEPRE1 的一个起始突变，该突变会导致 AA 和西非人致命的隐性成骨不全症 (OI)；据报道，胶原蛋白折叠正常的 OI 患者缺乏亲环蛋白 B；并在 BBS5 中发现了两种新的错义突变，它们具有致病特性，并对非洲人的 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”。我们从全球 163 个样本中调查了 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解释血统在历史、法医学、健康、和药品标签。