TOPMed Omics of Type 2 Diabetes and Quantitative Traits

项目总结/摘要 2型糖尿病继续在全球范围内传播，这是由于不健康的环境与遗传相互作用。最近的基因 在与2型糖尿病（T2 D）及其相关的数量性状（QTs： 空腹血糖（FG）、胰岛素（FI）和血红蛋白A1 c（A1 c））提供了对新的T2 D病理学的深入了解。但大多数 在白人中的发现;需要在受T2 D影响不成比例的少数群体中进行研究。此外，大多数 关联在非编码基因组中，这表明需要全基因组序列（WGS）分析以获得完整的基因组序列。 变体和效应基因表征。NHLBI精准医学跨组学（TOPMed）研究包括 来自五个人群的21，493例T2 D流行病例和63，541例对照的WGS（41，557欧元，23，203 AA，16，213 拉丁裔，2，867名亚洲人，1，194名萨摩亚肥胖研究），来自28个队列和多达54，407名非T2 D FG患者， FI或HbA 1c，以及T2 D发作的年龄、血糖控制水平和T2 D事件的纵向随访 事件在这个项目中，目标1是在五个祖先群体中测试WGS范围内的已知和新的常见和罕见变异 相关的T2 D和QT。我们将在NHLBI BioData Catalyst中进行分析。新变异体的复制是 来自6个T2 D生物库的> 100万不同血统的个体（UKBB、BioME、BioVU、Partners BB，REGARDS，MVP）与TOPMed-插补的基因组阵列数据。对于健康翻译，我们将T2 D遗传分组 将风险变体转化为多基因风险评分（PRS），以预测未来的T2 D或表征特定的生理轴，以及 在疾病因果关系的孟德尔随机化（MR）测试中使用变体。接下来，TOPMed有血液组学测量 来自五个祖先群体，也可能确定与T2 D病理生物学相关的新生物网络，包括 全血DNA甲基化（通过测序或微阵列测量，N= 11，131），转录组学（RNA-seq） （N= 8，334）、蛋白质组学（SomaLogic适体或Olink蛋白质组学，N= 7，897）和代谢组学（液体 色谱/质谱，N= 11，631）。在目标2中，我们将测试与T2 D和QT相关的组学特征 在T2 D的病理生物学的多维组学和基因组网络模型中。最后，在Aim 3中 我们计划将TOPM的WGS和组学结果与定制的细胞或组织特异性（β细胞、胰岛、肝脏、脂肪和 肌肉）组学和表观基因组注释（ATAC-seq，RNA-seq，Hi-C，ChIP-seq）在加速医学 合作伙伴关系（AMP）T2 D糖尿病epiGenome图谱，并与数百个额外的基因组性状协会在 AMP T2 D知识门户（T2 DKP），用于“计算机模拟变体-功能”和表型研究。完整的功能 利用人T2 D和QT基因组的血液和组织特异性组学整合的作图即将出现。我们 一个多学科、多中心的团队在遗传学和组学发现方面有着良好的记录。我们正在积极努力 使用TOPMed、AMP T2 D DGA和T2 DKP数据。我们有能力实现建议的目标， 我们打算寻找新的方法来解决T2 D在所有高危人群中的全球流行病。

Project Summary/Abstract Type 2 diabetes continues to spread globally due to unhealthy environment interacting with genetics. Recent genetic discoveries of >700 variants at >400 loci associated with type 2 diabetes (T2D) and its related quantitative traits (QTs: fasting glucose (FG), insulin (FI) and hemoglobin A1c (A1c)) give insight into new T2D pathobiology. However, most discoveries have been in whites; studies in minority groups disproportionately affected by T2D are needed. Also, most associations are in the non-coding genome, indicating that whole genome sequence (WGS) analysis is needed for full variant and effector gene characterization. The NHLBI Trans-Omics for Precision Medicine (TOPMed) study includes WGS from 21,493 cases of prevalent T2D and 63,541 controls from five populations (41,557 Euro, 23,203 AA, 16,213 Latino, 2,867 Asian, 1,194 Samoan Adiposity Study) from 28 cohorts and up to 54,407 non-T2D individuals with FG, FI or HbA1c, as well as age of T2D onset, level of glycemic control and longitudinal follow-up for incident T2D events. In this project Aim 1 is to test WGS-wide in five ancestry groups for known and new common and rare variants associated T2D and QTs. We will conduct analyses in the NHLBI BioData Catalyst. Replication of novel variants is available in >1 million individuals of diverse ancestry from six biobanks with T2D (UKBB, BioME, BioVU, Partners BB, REGARDS, MVP) with TOPMed-imputed genomic array data. For health translation, we will group T2D genetic risk variants into polygenic risk scores (PRSs) that predict future T2D or characterize specific physiological axes, and use variants in Mendelian Randomization (MR) tests of disease causality. Next, TOPMed has blood omic measures from five ancestry groups that may also identify novel biological networks relevant to T2D pathobiology, including whole blood DNA methylation (measured by sequencing or microarrays, N=11,131), transcriptomics (RNA-seq) (N=8,334), proteomics (SomaLogic aptamers or Olink proteomics, N=7,897) and metabolomics (liquid chromatography/mass spectroscopy, N=11,631). In Aim 2, we will test omic signatures associated with T2D and QTs individually and in multidimensional omic and genomic network models of the pathobiology of T2D. Finally, in Aim 3 we plan to integrate TOPMed WGS and omic results with bespoke cell or tissue-specific (beta cell, islet, liver, fat and muscle) omic and epigenomic annotation (ATAC-seq, RNA-seq, Hi-C, ChIP-seq) in the Accelerating Medicine Partnership (AMP) T2D Diabetes epiGenome Atlas, and with hundreds of additional genomic trait associations in the AMP T2D Knowledge Portal (T2DKP) for ‘in silico variant-to-function’ and phenomic studies. Complete functional mapping with blood and tissue-specific omic integration of the human T2D and QT genome is on the horizon. Our multidisciplinary, multicenter team has a proven track record in genetics and omic discovery. We are actively working with TOPMed, AMP T2D DGA and T2DKP data. We are well positioned to achieve the Aims of the proposal, with the intention to find new approaches to address the global epidemic of T2D in all populations at risk.