Genetic epidemiology of complex diseases

复杂疾病的遗传流行病学

基本信息

批准号：
7734929
负责人：
Charles Rotimi
金额：
$ 170万
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/7734929
关键词：
5q31 Admixture Africa African African American Age American Area Base Pairing Bioinformatics Biological Biomedical Research Boston Candidate Disease Gene Chromosome Mapping Chromosomes Clinical Collaborations Complex Custom DNA DNA Resequencing Data Databases Diabetes Mellitus Disease Disease susceptibility District of Columbia Doctor of Philosophy Elephantiasis Employee Strikes Enrollment Environment Environmental Risk Factor Ethiopia Etiology Functional disorder Genes Genetic Genetic Markers Genetic Models Genome Genomics Genotype Grant Health Height Home environment Human Human Genome Hypertension Individual Inherited Institutes International Knowledge Life Style Light Manuscripts Maps Methods Mission Modeling Mutation Detection National Institute of Diabetes and Digestive and Kidney Diseases Numbers Obesity Pattern Pharmaceutical Preparations Phenotype Play Policies Population Predisposition Procedures Process Research Research Personnel Resources Role Sampling San Francisco Scientist Services Soil Staging Students Susceptibility Gene Thinking Training Programs Translating United States National Institutes of Health Universities Variant Woman Women&apos s Health Work case control clay cohort density genetic epidemiology genetic selection genetic variant genome wide association study health disparity human disease metropolitan novel programs response

项目摘要

Genome Wide Association Studies (GWAS): In collaboration with investigators at the Coriell Institute for Biomedical Research, the CRGGH lab has successfully completed a genome-wide scan of over 2000 African Americans using the Affymetrix Genome-Wide Human SNP Array 6.0 with 1.8 million genetic markers ( equal number of SNPs and CNVs). Investigators at the center are currently analyzing generated data on multiple phenotypes including obesity, hypertension, diabetes and height. Resulting manuscripts are at different stages of completion. Fine-mapping of Diabetes Genes: The CRGGH lab is conducting fine mapping of a linkage region on chromosome 5q22-5q31 (109055750 128436401 base pairs). Genotyping for this project was conducted by the Center for Inherited Disease Research (CIDR) using the Illumina Custom infinium II BeadChip. A total of 1,536 SNPs were attempted and 1,496 SNPs were released. In addition, we used the Imputation procedure to imputed genotypes using the HapMap release #22 in 60 YRI (Yoruba) founder. This procedure increased the number of SNPs from 1,496 to over 22,000 resulting in much denser genetic map ( 1kb density from about 11kb). We have completed analyses of this project and we have identified exciting novel genetic variants for obesity and diabetes that promises to share light on pathophysiology of these human diseases. The manuscripts describing these findings are complete and we are awaiting the results of the replication projects in other populations. The initial results were presented recently in San Francisco during the 2008 American Diabetes Association annual meeting. Admixture Mapping for Hypertension Genes in African Americans The CRGGH lab is using the admixture mapping approach to identify regions of the genome that may harbor hypertension susceptibility genes in African Americans. We have genotyped a panel of over 3,000 ancestry informative markers in a well-characterized cohort of African Americans enrolled from the Washington, D.C. metropolitan area. This data is being analyzed by investigators at the CRGGH lab. Identified susceptibility loci will be subjected to fine mapping using very high density SNP panel selected from the HapMap database. In combination with bioinformatics methods, the CRGGH lab will use the data from the fine-mapping studies to identify genes to be resequenced for mutation detection and replication studies in multiple populations. Comprehensive Candidate Gene Approach to Identify Hypertension Susceptibility Genes in African Americans and African Populations - The CRGGH lab has completed a large-scale candidate genes study for hypertension (HTN) in African Americans and multiple African populations. A total number of 1598 subjects (comprising 1002 African Americans and 562 West Africans) have been genotyped using Illuminas custom SNP GoldenGate genotyping platform. Given the poor consistency of candidate gene studies for HTN, we gave careful thought to the selection of genetic variants represented in the final custom panel of 768 SNPs. Investigators in the center are using the case-control associations strategy, under various genetic models, to identify susceptibility variants to HTN. Genetics of Podoconiosis: In collaboration with scientists from Ethiopia and the UK, CRGGH investigators are conducting the first genetic epidemiology to unravel the complex interaction between genes and environment in the etiology of podoconiosis (endemic non-filarial elephantiasis). Podoconiosis is a geochemical disease occurring in individuals exposed to red clay soil derived from alkalic volcanic rock. One of the striking features of podoconiosis is that only a small proportion of individuals who are exposed to red clay develop disease. The field work for this project is complete and DNA samples are being prepared for shipment to a commercial genotyping facility. Resulting data will be used as PhD thesis for the Ethiopian Student in the CRGGH lab. The Black Women Health Study (BWHS) The CRGGH lab is collaborating with Boston University to develop a project to conduct genome-wide association study in 4,000 African American women (2,000 cases of diabetes and 2,000 controls) in the BWHS. The BWHS is a national longitudinal cohort of women assembled in 1995 to study causes of illness in black women. It includes 59,000 women aged 21-69 at baseline. Dr. Rotimis lab was responsible for receiving, isolating and tracking DNA samples on these women. Over 25,000 DNA samples have been processed to date. An R01 grant has been submitted to NIDDK to conduct GWAS in 2000 cases of diabetes and 2000 controls.

全基因组关联研究 (GWAS)：CRGGH 实验室与 Coriell 生物医学研究所的研究人员合作，使用 Affymetrix 全基因组人类 SNP 阵列 6.0（包含 180 万个基因）成功完成了对 2000 多名非裔美国人的全基因组扫描。标记（SNP 和 CNV 数量相同）。该中心的研究人员目前正在分析生成的多种表型数据，包括肥胖、高血压、糖尿病和身高。最终的手稿处于不同的完成阶段。糖尿病基因精细定位：CRGGH实验室正在对染色体5q22-5q31上的连锁区域（109055750 128436401碱基对）进行精细定位。该项目的基因分型由遗传性疾病研究中心 (CIDR) 使用 Illumina Custom infinium II BeadChip 进行。总共尝试了 1,536 个 SNP，并发布了 1,496 个 SNP。此外，我们使用 60 YRI（约鲁巴）创始人的 HapMap 版本 #22，使用插补程序来插补基因型。该过程将 SNP 的数量从 1,496 个增加到 22,000 个以上，从而产生更密集的遗传图谱（密度从约 11kb 增加到 1kb）。我们已经完成了对该项目的分析，并发现了令人兴奋的肥胖和糖尿病的新型遗传变异，有望为这些人类疾病的病理生理学提供线索。描述这些发现的手稿已经完成，我们正在等待其他人群中复制项目的结果。初步结果最近在旧金山举行的 2008 年美国糖尿病协会年会上公布。非裔美国人高血压基因的混合图谱 CRGGH 实验室正在使用混合图谱方法来识别非裔美国人中可能含有高血压易感基因的基因组区域。我们对来自华盛顿特区都会区的一组特征明确的非裔美国人中的 3,000 多个血统信息标记进行了基因分型。 CRGGH 实验室的研究人员正在分析这些数据。将使用从 HapMap 数据库中选择的非常高密度的 SNP 组对已识别的易感性位点进行精细作图。结合生物信息学方法，CRGGH 实验室将利用精细作图研究的数据来识别需要重新测序的基因，以便在多个人群中进行突变检测和复制研究。用于识别非裔美国人和非洲人群高血压易感基因的综合候选基因方法 - CRGGH 实验室已经完成了针对非裔美国人和多个非洲人群的高血压 (HTN) 的大规模候选基因研究。使用 Illuminas 定制 SNP GoldenGate 基因分型平台对总共 1598 名受试者（包括 1002 名非裔美国人和 562 名西非人）进行了基因分型。鉴于 HTN 候选基因研究的一致性较差，我们仔细考虑了 768 个 SNP 的最终定制面板中代表的遗传变异的选择。该中心的研究人员正在各种遗传模型下使用病例对照关联策略来识别 HTN 的易感性变异。足足病的遗传学：CRGGH 研究人员与埃塞俄比亚和英国的科学家合作，正在进行首次遗传流行病学研究，以揭示足足病（地方性非丝虫象皮病）病因学中基因与环境之间复杂的相互作用。脚足病是一种地球化学疾病，发生在暴露于碱性火山岩红粘土的个体中。脚足病的显着特征之一是，只有一小部分接触红粘土的人会患病。该项目的现场工作已经完成，DNA 样本正在准备运送到商业基因分型设施。所得数据将用作 CRGGH 实验室埃塞俄比亚学生的博士论文。黑人女性健康研究 (BWHS) CRGGH 实验室正在与波士顿大学合作开发一个项目，对 BWHS 的 4,000 名非裔美国女性（2,000 名糖尿病患者和 2,000 名对照者）进行全基因组关联研究。 BWHS 是 1995 年组建的全国女性纵向队列，旨在研究黑人女性的疾病原因。其中包括 59,000 名基线年龄在 21 岁至 69 岁之间的女性。 Rotimis 博士实验室负责接收、分离和追踪这些女性的 DNA 样本。迄今为止，已处理了超过 25,000 个 DNA 样本。已向 NIDDK 提交 R01 拨款，用于对 2000 例糖尿病病例和 2000 例对照病例进行 GWAS。