Genome-wide meta-analysis for severe diabetic retinopathy

• Published in: Human molecular genetics Vol. 20; no. 12; pp. 2472 - 2481
• Main Authors: Grassi, M. A., Tikhomirov, A., Ramalingam, S., Below, J. E., Cox, N. J., Nicolae, D. L.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.06.2011
• Subjects: Association analysis; Association Studies; Biological and medical sciences; Blindness; Chromosome 1; chromosome 16; Cohort Studies; copy number; Data processing; Diabetes mellitus; Diabetes Mellitus, Type 1 - complications; Diabetes. Impaired glucose tolerance; Diabetic Retinopathy - etiology; Diabetic Retinopathy - genetics; DNA Copy Number Variations; Edema; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Epidemiology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Genetic Loci - genetics; Genetic Predisposition to Disease - genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Histone acetyltransferase; Humans; Introns; Kidney; Medical sciences; Molecular and cellular biology; Nephropathy; Phenotype; Polymorphism, Single Nucleotide - genetics; Replication; Retinopathy; Reviews; Single-nucleotide polymorphism; Endocrinopathy; Eye disease; Retinopathy; Diabetes mellitus; Genetics; Severe; Metaanalysis
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddr121

Diabetic retinopathy is a leading cause of blindness. The purpose of this study is to identify novel genetic loci associated with the sight threatening complications of diabetic retinopathy. We performed a meta-analysis of genome-wide association data for severe diabetic retinopathy as defined by diabetic macular edema or proliferative diabetic retinopathy in unrelated cases ascertained from two large, type I diabetic cohorts: the Genetics of Kidney in Diabetes (GoKinD) and the Epidemiology of Diabetes Intervention and Control Trial (EDIC) studies. Controls were other diabetic subjects in the cohort. A combined total of 2829 subjects (973 cases, 1856 controls) were studied on 2 543 887 single nucleotide polymorphisms (SNPs). Subjects with nephropathy were excluded in a sub-analysis of 281 severe retinopathy cases. We also performed an association analysis of 1390 copy number variations (CNVs) using tag SNPs. No associations were significant at a genome-wide level after correcting for multiple measures. The meta-analysis did identify several associations that can be pursued in future replication studies, including an intergenic SNP, rs476141, on chromosome 1 (P-value 1.2 × 10(-7)). The most interesting signal from the CNV analysis came from the sub-group analysis without nephropathy subjects and is rs10521145 (P-value 3.4 × 10(-6)) in the intron of CCDC101, a histone acetyltransferase. This SNP tags the copy number region CNVR6685.1 on chromosome 16 at 28.5 Mb, a gain/loss site. In summary, this study nominates several novel genetic loci associated with the sight-threatening complications of diabetic retinopathy and anticipates future large-scale consortium-based validation studies.