Genome-wide meta-analysis for severe diabetic retinopathy

Abstract

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.

Figure 1.

Manhattan plot summarizing results of the genome-wide association meta-analysis. Each dot represents a SNP, plotted by its chromosomal location (x-axis) and its associated P-value (y-axis). Hence, each point signifies an examined SNP's genomic location in the imputed data set plotted in relation to its P-value.

Figure 2.

Plot of genomic region around the SNP rs476141. The figure reveals the location of most significant SNPs in relation to neighboring genes. SNPs in LD with the SNP rs476141 (r² 0.8–1.0) are colored in red. Gene location and exons are indicated above figure. Association in the region generated by Haploview is shown by LD plot below the figure. Figure created using genome build 36.

Figure 3.

Plot of the genomic region around CNVR6685.1. The figure reveals the location of the SNP rs10521145 (arrow) in relation to SULT1A1, SULT1A2, CCDC101 and CNVR6685.1. SNPs in LD with rs10521145 (r² 0.8–1.0) are colored in red. Gene location and exons are indicated above figure. Association in the region generated by Haploview is shown by LD plot below the figure. Figure created using genome build 36.