Multi-ethnic GWAS of diabetic retinopathy: enhanced power using new methods

描述(申请人提供)：糖尿病视网膜病变(DR)是美国工作年龄失明的主要原因。有证据表明DR与遗传有关。DR的遗传率估计高达27%。到目前为止，只发现了几个可能导致DR的基因。这在一定程度上是因为到目前为止，对DR的基因研究包含的参与者数量有限。组合和分析来自不同种族/民族的样本的新方法提供了一个机会，可以提高我们检测与DR假说相关的基因的能力：组合来自多个群体的参与者的基因样本将提高发现DR基因的能力。使用新的混合关联、协变量建模和精细定位方法将进一步最大限度地提高检测相关基因的能力。具体目标：1.通过利用非裔美国人(AA)和高加索人糖尿病受试者的现有数据进行全基因组关联研究(GWAS)，并将混合关联纳入GWAS，以确定与DR相关的遗传变异。2.通过使用责任阈值模型将关于参与者的糖尿病病程和血糖控制情况的信息纳入GWAS，以增加基因发现的能力。3.利用来自其他种族/民族的DR参与者的现有遗传数据，复制和绘制最有希望的关联。方法：来自2型糖尿病患者(T2D)和DR表型的多个AA和高加索人群的现有全基因组基因分型数据将使用新的统计方法进行联合分析，将单核苷酸多态关联和混合关联信号结合起来，以提高能力。将患有T2D和无DR的个体与使用早期治疗糖尿病视网膜病变研究量表定义的T2D和DR的个体进行比较。随后，关于糖尿病病程和血糖控制这两个主要的非遗传DR协变量的数据将通过责任阈值建模纳入AA和高加索人的联合GWA值。最后，将在包括南亚人和东亚人在内的其他人群的队列中复制来自GWAS分析的一组全基因组显著的或暗示的变异(P-Value&lt；10-5)。所有在复制分析后达到全基因组意义的信号都将被带入精细作图。将使用对HapMap 3和1000个基因组变种的基因分型和归因的跨群体荟萃分析，在没有任何额外基因分型的情况下进行精细作图，应用为跨群体精细作图开发的新指标和方法，以最佳地利用不同群体中不同的连锁不平衡模式。含义：如果与DR相关的基因被识别出来，它们将提供对病理生理学的洞察，并可能导致DR的新疗法。此外，结果可能提供信息，以建议糖尿病患者关于他们患DR的风险。 公共卫生相关性：糖尿病是导致失明的常见原因，我们仍然不完全了解糖尿病是如何导致眼睛损伤的。我们的研究旨在揭示糖尿病眼病或糖尿病视网膜病变的遗传风险因素。所获得的见解可以改进糖尿病视网膜病变的治疗，以及对糖尿病患者关于其发展为糖尿病视网膜病变的风险的咨询。

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is the leading cause of blindness in working-age Americans. There is evidence for a genetic contribution to DR~ the heritability of DR has been estimated to be as high as 27%. To date, only a few genes that might contribute to DR have been discovered. This is in part because genetic studies of DR have thus far contained limited numbers of participants. New methods of combining and analyzing samples from different racial/ethnic groups provide an opportunity to increase our ability to detect genes associated with DR. Hypotheses: Combining genetic samples from participants from multiple populations will increase the ability to discover DR genes. Use of novel admixture association, covariate modeling and fine-mapping methods will further maximize the power to detect associated genes. Specific Objectives: 1. To identify genetic variants associated to DR by performing a genome-wide association study (GWAS) using existing data from African American (AA) and Caucasian diabetic subjects and by incorporating admixture association into the GWAS. 2. To increase the power of genetic discovery by incorporating information about the participants' duration of diabetes and glycemic control into the GWAS using liability threshold modeling. 3. To replicate and fine-map the most promising associations using existing genetic data from DR participants from additional racial/ethnic groups. Methods: Existing genome-wide genotyping data from multiple AA and Caucasian cohorts of individuals with type 2 diabetes (T2D) and DR Phenotyping will be jointly analyzed using new statistical methods to combine single nucleotide polymorphism association and admixture association signals for increased power. Individuals with T2D and no DR with be compared to individuals with T2D and DR defined using the Early Treatment Diabetic Retinopathy Study scale. Subsequently, data on the two major non-genetic DR covariates, duration of diabetes and glycemic control, will be incorporated into the combined AA and Caucasian GWAS via liability threshold modeling. Finally, a set of genome-wide significant or suggestive variants (P-value < 10-5) from the GWAS analyses will be replicated in cohorts from additional populations, including South Asians and East Asians. All signals that attain genome-wide significance after replication analyses will be carried forward to fine-mapping. Fine-mapping will be performed without any additional genotyping using cross-population meta-analysis of genotyped and imputed HapMap 3 and 1000 Genomes variants, applying new metrics and methods developed for cross-population fine-mapping that optimally leverage the different patterns of linkage disequilibrium in different populations. Implications: If genes associated with DR are identified, they will provide insights into pathophysiology and may lead to new therapies for DR. In addition, results may provide information with which to counsel diabetic patients regarding their risk of DR. PUBLIC HEALTH RELEVANCE: Diabetes is a common cause of blindness, and we do still do not completely understand how diabetes causes eye damage. Our study aims to uncover the genetic risk factors for diabetic eye disease, or diabetic retinopathy. The insights gained could improve the treatment of diabetic retinopathy as well as the counseling of diabetic patients regarding their risk of developing diabetic retinopathy.