Genetic epidemiology of complex diseases

复杂疾病的遗传流行病学

基本信息

批准号：
10931301
负责人：
Charles Rotimi
金额：
$ 349.11万
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/10931301
关键词：
Adipocytes Adipose tissue Africa African African American African American population Alcohol consumption Attention Biological Biological Markers Biological Process Blood Blood Pressure Blood specimen CRISPR/Cas technology Cardiometabolic Disease Cholesterol Chromatin Chromosome Mapping Clinical Complex Congresses DNA Methylation DNA analysis Data Dedications Developing Countries Diabetes Mellitus Disease Disease susceptibility Endothelial Cells Enteroendocrine Cell Environmental Risk Factor Ethnic Origin Ethnic Population Etiology European European ancestry Family Study Functional disorder G6PC2 gene Gene Frequency Genes Genetic Genetic Models Genetic Risk Genetic Variation Genetic study Genome Genomic approach Genomics Gluconeogenesis Glucose Glycolysis Goals Health High Density Lipoprotein Cholesterol High Density Lipoproteins Home Human Human Genetics Human Genome Human papilloma virus infection Hypertension Individual Insulin Resistance International Islets of Langerhans Joints Kidney Diseases Knowledge LDL Cholesterol Lipoproteins Least-Squares Analysis Life Style Lipids Liver Longitudinal Studies Low-Density Lipoproteins Mendelian randomization Metabolic Diseases Methylation Migrant Mission Modeling Nigeria Non-Insulin-Dependent Diabetes Mellitus Obesity Overweight Paper Participant Pathogenesis Pathway interactions Pattern Pharmaceutical Preparations Phenotype Physical activity Plasma Play Policies Population Population Heterogeneity Positioning Attribute Postdoctoral Fellow Predisposition Proteomics Protocols documentation Publishing Reporting Research Research Personnel Resources Risk Risk Factors Role Sampling Science Scientist Services Signal Transduction Skeletal Muscle Smoking South Africa Stroke Students Tissue Banks Tissues Training Training Programs Translating Triglycerides United States National Institutes of Health Universities Untranslated RNA Variant Weight Work adiponectin analytical tool bead chip blood lipid cardiometabolic risk cardiometabolism cell type clinical care cohort disparity elimination disparity reduction epidemiologic data epidemiological model epigenome-wide association studies ethnic difference ethnic diversity fasting glucose functional genomics genetic epidemiology genome resource genome sciences genome sequencing genome wide association study genome-wide genomic data global health health disparity health inequalities improved insight insulin secretion men metabolomics methylation pattern molecular phenotype multi-ethnic multiple omics non-diabetic novel obese person polygenic risk score programs response risk variant sedentary lifestyle single nucleus RNA-sequencing social culture trait transcriptome sequencing transcriptomics whole genome working group

项目摘要

Current activities within the Center for Research on Genomics and Global Health (CRGGH) build on the more than three 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 Center's work. We continue to advance our science at the NIH through our work on the genetic epidemiology of complex disease, focusing on generating insights and contributions from studies of genetics of cardiometabolic disorders in African populations. The current longitudinal study in Nigeria, an extension of the African America Diabetes Mellitus (AADM) study, is collecting and analyzing phenotypic, biomarker, genomic, transcriptomic, metabolomic, and other data to build a comprehensive picture of the etiopathogenesis of T2D in Africa. In the current reporting period, we made substantial progress in these multi-omics studies of our deeply phenotyped T2D cohort in Africa. Whole genome sequencing of the samples is now at an advanced stage with over 400 samples already sequenced by NISC. We have RNA-seq data on primary tissue (adipose tissue, skeletal muscle, blood) on over 50 participants and have generated whole genome methylation array data on 600 samples. We also have proteomic and metabolomics data on this cohort. We are currently optimizing protocols for generating snRNA-seq and snATAC-seq data from our primary tissue collection from Africa. We presented several aspects of this project at the 14th International Congress of Human Genetics in Cape Town, South Africa, in February 2023. The first set of papers describing the results are currently under review. These data will fill several important gaps in our knowledge of the these molecular phenotypes in understudied populations and generate resources for use by scientists working in the field. We continue to participate in multiple active protocols including several H3Africa Consortium projects (including projects on type 2 diabetes, stroke, renal disorders and human papilloma virus infection), the multi-ethnic CHARGE Gene x Lifestyle Working Group and Research on Obesity and Diabetes among African Migrants (RODAM) study (among others). Our studies of T2D and related traits include an analysis of 9,232 individuals of European ancestry (PMID: 35657990) in which we showed that three known glucose-associated loci (in GCKR, G6PC2 and SLC30A8) were independently associated with fasting glucose at genome-wide significant levels. We replicated this association in a trans-ethnic analysis of 14,303 individuals and showed that the joint effect of the three SNPs was a reduced T2D risk. The findings indicate additive effects across pathophysiological pathways involved in type 2 diabetes, including glycolysis, gluconeogenesis, and insulin secretion. We reported an epigenome-wide association study of insulin resistance in African Americans (PMID: 35836279). Using DNA methylation profiles of blood samples obtained from the Illumina Infinium HumanMethylation450 BeadChip, we analyzed DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men from the Howard University Family Study. We identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR, one of which is a known locus while the other two DMPs are novel. The two novel DMPS are either in genes previously associated with insulin resistance and T2D in Europeans or have been implicated in biological processes relevant to insulin resistance. We also found low transferability of HOMA-IR DMPs reported in other populations in this cohort of African Americans. The findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. We participated in the largest genomic analyses for T2D globally (PMID: 37034649) that involved over 2.5 million individuals (39.7% non-European ancestry), including 428,452 T2D cases. The study identified 1,289 independent association signals (611 loci) at genome-wide significance of which 145 loci were novel. Eight non-overlapping clusters of T2D signals with distinct profiles of cardiometabolic trait associations were identified, and each cluster was differentially enriched for cell-type specific regions of open chromatin in pancreatic islets, adipocytes, endothelial, and enteroendocrine cells(PMID: 37034649). We participated in a massive international consortium that did multi-ethnic, multi-layer functional genomic analyses to understand noncoding genetic variation in lipids (PMID: 35931049). The effort involved integrating a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with several functional genomic datasets to discover regulatory mechanisms. The findings confirmed the central role of the liver in lipid levels and showed the selective enrichment of adipose-specific chromatin marks in HDL-cholesterol and triglycerides. In our African cohort, we conducted a Mendelian randomization study for a causal relationship between adiponectin and LDL cholesterol (PMCID: PMC9643497). We utilized a polygenic risk score (PRS) for adiponectin levels as the instrumental variable in two-stage least-squares MR analysis to assess its association with insulin resistance, HDL, LDL, total cholesterol, triglycerides, blood pressure, T2D, and hypertension. The adiponectin PRS was causally related with LDL but not the other traits. This association was observed was only statistically significant among overweight/obese individuals. In normal weight individuals, the adiponectin PRS was also associated with T2D, and (in men only) with HDL. Thus study is the first MR study for adiponectin in sub-Saharan Africans and the findings support a causal relationship of adiponectin with LDL, with T2D in normal weight individuals only, and with HDL in men only. We also participated in other consortial studies that examined gene-by-lifestyle interactions with smoking and alcohol consumption (PMID: 36544485) and GWAS of physical activity and sedentary behavior (PMID: 36071172). We published the first epigenome-wide association study of plasma lipids in West Africans working with the RODAM study (PMID: 36791658) and We also published an important paper that showed ancestral and environmental patterns in the association between triglycerides and other cardiometabolic risk factors (PMID:370043).

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三十年研究，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调查人员致力于对各种祖先人群进行原始研究，开发公开可用的国际基因组资源和分析工具，以增加跨种族基因映射，并培训来自不同种族背景的科学家（请参阅http://crggh.nih.gov/compermission.gov/mission.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，结合了新的进步，例如OMIC数据和CRISPR/CAS9技术的整合到中心的工作中。我们通过关于复杂疾病的遗传流行病学的工作继续推进NIH的科学，重点是从非洲人群中心脏代谢疾病的遗传学研究产生见解和贡献。当前在尼日利亚的纵向研究是非洲美国糖尿病（AADM）研究的扩展，正在收集和分析表型，生物标志物，基因组，转录组，代谢组和其他数据，以构建非洲T2D病情发生的全面图片。在当前的报告期间，我们在这些对非洲深层表型T2D队列的多摩学研究中取得了重大进展。样品的整个基因组测序现在处于高级阶段，已有400多个样品已经由NISC测序。我们在50多名参与者的原代组织（脂肪组织，骨骼肌，血液）上有RNA-Seq数据，并在600个样品上产生了整个基因组甲基化阵列数据。我们在该队列上还具有蛋白质组学和代谢组学数据。我们目前正在优化从非洲的主要组织收集中生成SNRNA-SEQ和SNATAC-SEQ数据的方案。我们在2023年2月在南非开普敦举行的第14届国际人类遗传学大会上介绍了该项目的几个方面。描述结果的第一篇论文目前正在审查中。这些数据将填补我们对研究不足的人群中这些分子表型的了解，并生成用于该领域工作的科学家使用的资源。我们将继续参与多种主动方案，包括几个H3AFRICA联盟项目（包括有关2型糖尿病，中风，肾脏疾病和人类乳头状瘤病毒感染的项目），多种种族费用Gene X Lifestyle工作组以及有关非洲移民（RODAM）研究的肥胖和糖尿病研究（其他）。我们对T2D和相关性状的研究包括对9,232个欧洲血统个体（PMID：35657990）的分析，其中我们表明，三个已知的葡萄糖相关基因座（在GCKR，GCKR，G6PC2和SLC30A8中）与在基因组含量显着水平上的禁食葡萄糖独立相关。我们在对14,303个人的跨种族分析中复制了这种关联，并表明三个SNP的关节效应是T2D风险的降低。研究结果表明，涉及2型糖尿病的病理生理途径的加性作用，包括糖酵解，糖生成和胰岛素分泌。我们报道了非裔美国人胰岛素抵抗的一项表观基因组的关联研究（PMID：35836279）。利用从Illumina Infinium humbhymethylation获得的血液样本的DNA甲基化谱450珠奇普，我们分析了136名来自霍华德大学家庭研究的136名非糖尿病，无关的非裔美国人男性中与胰岛素抵抗相关的DNA甲基化基因座。我们确定了三个差异的甲基化位置（DMP），用于在5％FDR处的胰岛素抵抗（HOMA-IR）评估，其中一个是已知的基因座，而其他两个DMP是新颖的。这两个新型的DMP要么以前与欧洲人的胰岛素抵抗和T2D相关的基因，要么与与胰岛素耐药有关的生物学过程涉及。我们还发现，在这个非洲裔美国人群中，其他人群中报告了HOMA-IR DMP的可转移性低。我们研究的发现表明，与种群中胰岛素抵抗相关的DNA甲基化模式存在实质性差异。我们参加了全球T2D的最大基因组分析（PMID：37034649），其中涉及超过250万个人（39.7％的非欧洲血统），其中包括428,452 T2D病例。该研究确定了1,289个独立关联信号（611个基因座），其全基因组意义，其中145个基因座是新颖的。鉴定了八个非重叠的T2D信号簇，并鉴定出具有不同的心脏代谢性状关联曲线，并且在胰岛，脂肪细胞，脂肪细胞，脂肪细胞和肠endocrine细胞中的开放式染色质质特定区域均具有差异化的细胞类型特定区域。我们参加了一个大规模的国际财团，该联盟进行了多种族的多层功能基因组分析，以了解脂质中的非编码遗传变异（PMID：35931049）。这项工作涉及将大型GWA纳入血脂上，涉及来自五个祖先的160万个人，并与几个功能性基因组数据集进行发现，以发现调节机制。研究结果证实了肝脏在脂质水平中的核心作用，并显示了HDL-胆固醇和甘油三酸酯中脂肪特异性染色质标记的选择性富集。在我们的非洲队列中，我们进行了一项孟德尔随机研究，以实现脂联素和LDL胆固醇之间的因果关系（PMCID：PMC9643497）。我们利用脂联素水平的多基因风险评分（PR）作为两阶段最小二乘MR分析中的仪器变量，以评估其与胰岛素抵抗，HDL，LDL，总胆固醇，甘油三酸酯，血压，血压，T2D和高血压的关联。脂联素PR与LDL有因果关系，但与其他特征无关。观察到这种关联仅在超重/肥胖个体中具有统计学意义。在正常体重个体中，脂联素PRS也与T2D有关，并且（仅在男性中）与HDL有关。因此，研究是撒哈拉以南非洲人脂联素的首次MR研究，研究结果支持脂联素与LDL的因果关系，仅在正常体重个体中与T2D，仅在男性中与HDL。我们还参加了其他联盟研究，这些研究研究了与吸烟和饮酒的基因相互作用（PMID：36544485）和体育活动和久坐行为的GWA（PMID：36071172）。我们发表了第一项与Rodam研究（PMID：36791658）的西非人血浆脂质的首次均基因组脂质研究，我们还发表了一篇重要论文，该论文显示了甘油三酸酯和其他心脏代谢风险因素（PMID：370043）之间的祖先和环境模式。

项目成果

期刊论文数量（46）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A UGT1A1 variant is associated with serum total bilirubin levels, which are causal for hypertension in African-ancestry individuals.

DOI：
10.1038/s41525-021-00208-6
发表时间：
2021-06-11
期刊：
NPJ genomic medicine
影响因子：
5.3
作者：
Chen G;Adeyemo A;Zhou J;Doumatey AP;Bentley AR;Ekoru K;Shriner D;Rotimi CN
通讯作者：
Rotimi CN

Genome-wide association study of prevalent and persistent cervical high-risk human papillomavirus (HPV) infection.

DOI：
10.1186/s12881-020-01156-1
发表时间：
2020-11-23
期刊：
BMC medical genetics
影响因子：
0
作者：
Adebamowo SN;Adeyemo AA;Rotimi CN;Olaniyan O;Offiong R;Adebamowo CA;H3Africa ACCME Research Group
通讯作者：
H3Africa ACCME Research Group

Health disparities in the genomic era: the case for diversifying ethnic representation.