A functional genomics pipeline for genetic discovery in diabetic kidney disease

摘要 糖尿病肾病（DKD）是一种破坏性的微血管并发症， 2型糖尿病（T2 D）它已被证明有一个遗传的组成部分，但先前的搜索， 因为这种疾病的遗传决定因素已经取得了有限的成功。在遗传学中， 肾病-一个国际努力（GENIE）联盟，女王大学 贝尔法斯特大学、都柏林大学、赫尔辛基大学、密歇根大学、 宾夕法尼亚大学和布罗德研究所，我们利用了一个持续的共同资助机制， 在爱尔兰，北方爱尔兰和美国之间。这个国际基因组联盟 一个更大的糖尿病肾病合作研究计划， 收集了来自T1 D参与者的近20，000份样本，有和没有肾脏疾病。 我们进行了一项全基因组关联研究（GWAS），发现了16个新的信号， 全基因组意义最强的信号集中在保护性的错义编码上 COL 4A 3变异，编码肾小球基底的组成部分 膜，这涉及DKD的肾脏生物学方面。在这个奖项中，我们建议建立 在这一既定基础设施上，实现以下具体目标：（1）显著 通过纳入T2 D背景下约150，000例DKD样本来扩大样本量，从而 大大增加了我们发现T1 D中DKD的共同和独特风险因素的能力 和T2 D，并使用计算工具来获得对DKD发病机制的生物学见解;（2） 在外周血和人肾脏中生成全基因组表观基因组数据集， 告知遗传发现的相关性，使预测工具的建设，并推断 通过孟德尔随机化的因果关系;（3）创建一个实验管道， DKD的动物、细胞和类器官模型，以寻求有前途的遗传学的功能验证。 调查结果。这种多学科和协同研究小组正在进行的密切合作 应该推进我们对DKD分子决定因素的认识， 分子靶点的治疗，并促进临床预测。

ABSTRACT Diabetic kidney disease (DKD) is a devastating microvascular complication of both type 1 (T1D) and type 2 diabetes (T2D). It has been shown to have a heritable component, but prior searches for the genetic determinants of this condition have had limited success. In the Genetics of Nephropathy – an International Effort (GENIE) Consortium, a collaboration between Queen’s University Belfast, University of Dublin, University of Helsinki, University of Michigan, University of Pennsylvania and the Broad Institute, we have leveraged an ongoing co-funding mechanism between Ireland, Northern Ireland and the US. This international genomics consortium enucleated a larger Diabetic Nephropathy Collaborative Research Initiative, which coalesced to assemble nearly 20,000 samples from participants with T1D, with and without kidney disease. We performed a genome-wide association study (GWAS) and discovered 16 new signals at genome-wide significance. The strongest signal centered on a protective missense coding variant at COL4A3, which encodes an integral component of the glomerular basement membrane, implicating this aspect of kidney biology in DKD. In this award, we propose to build on this established infrastructure to undertake the following Specific Aims: (1) to significantly expand our sample size by including ~150,000 samples with DKD in the context of T2D, thereby substantially increasing our power to discover shared and distinct risk factors for DKD in T1D and T2D, and to use computational tools to derive biological insights into DKD pathogenesis; (2) to generate a genome-wide epigenomic dataset in both peripheral blood and human kidney to inform the relevance of genetic findings, enable the construction of predictive tools, and infer causality via Mendelian randomization; and (3) to create an experimental pipeline centered on animal, cellular and organoid models of DKD to pursue functional validation of promising genetic findings. This ongoing close collaboration of multidisciplinary and synergistic research groups should advance our knowledge of the molecular determinants of DKD, identify potential molecular targets for therapeutics, and facilitate clinical prediction.