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

描述（由申请人提供）：糖尿病视网膜病变（DR）是美国工作年龄段失明的主要原因。有证据表明，DR的遗传贡献-DR的遗传率估计高达27%。到目前为止，只有少数可能导致DR的基因被发现。这部分是因为迄今为止，DR的遗传研究仅包含有限数量的参与者。结合和分析来自不同种族/民族群体的样本的新方法提供了一个机会，以提高我们检测DR相关基因的能力。假设：结合来自多个人群的参与者的遗传样本将提高发现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。通过使用非裔美国人（AA）和高加索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，识别与DR相关的遗传变异。2.通过使用责任阈值模型将参与者的糖尿病持续时间和血糖控制信息纳入GWAS，以增加遗传发现的力量。 3.使用来自其他种族/民族的DR参与者的现有遗传数据复制和精细绘制最有希望的关联。研究方法：将使用新的统计方法联合分析来自患有2型糖尿病（T2 D）和DR表型的多个AA和高加索人队列的现有全基因组基因分型数据，以结合联合收割机单核苷酸多态性关联和混合关联信号，以提高功效。将患有T2 D且无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患有T2 D且DR的个体进行比较。随后，两个主要非遗传性DR协变量（糖尿病持续时间和血糖控制）的数据将通过责任阈值建模纳入合并的AA和高加索人GWAS中。最后，来自GWAS分析的一组全基因组显著或提示性变异（P值< 10-5）将在来自其他人群（包括南亚人和东亚人）的队列中重复。在复制分析后获得全基因组显著性的所有信号将被结转到精细定位。将使用基因分型和插补的HapMap 3和1000基因组变体的跨群体荟萃分析进行精细定位，无需任何额外的基因分型，采用为跨群体精细定位开发的新指标和方法，最佳地利用不同群体中的不同连锁不平衡模式。 含义：如果与DR相关的基因被确定，他们将提供深入了解病理生理学，并可能导致新的治疗DR。此外，结果可能提供信息，以咨询糖尿病患者关于他们的DR的风险。 糖尿病是一种常见的致盲原因，我们仍然不完全了解糖尿病如何导致眼睛损伤。 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善糖尿病视网膜病变的治疗以及糖尿病患者关于其患糖尿病视网膜病变风险的咨询。

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.