Genome-Wide Linkage Analyses to Identify Loci for Diabetic Retinopathy

Abstract

Hyperglycemia and long duration of diabetes are widely recognized risk factors for diabetic retinopathy, but inherited susceptibility may also play a role because retinopathy aggregates in families. A genome-wide linkage analysis was conducted in 211 sibships in which >2 siblings had diabetes and retinal photographs were available from a longitudinal study. These sibships were a subset of 322 sibships who had participated in a previous linkage study of diabetes and related traits; they comprised 607 diabetic individuals in 725 sibpairs. Retinal photographs were graded for presence and severity of diabetic retinopathy according to a modification of the Airlie House classification system. The grade for the worse eye was adjusted for age, sex, and diabetes duration and analyzed as a quantitative trait. Heritability of diabetic retinopathy in this group was 18% (95% CI 2-36). A genome-wide linkage analysis using variance components modeling found evidence of linkage on chromosome 1p. Using single-point analysis, the peak logarithm of odds (LOD) was 3.1 for marker D1S3669 (34.2 cM), whereas with multipoint analysis the peak LOD was 2.58 at 35 cM. No other areas of suggestive linkage were found. We propose that an area on chromosome 1 may harbor a gene or genes conferring susceptibility to diabetic retinopathy.

Genome-wide association studies: applications and insights gained in Ophthalmology

“…Two of these genes (ARHGAP22 and PLXDC2) are involved in endothelial cell angiogenesis. They also confirmed the results of a previous genomewide linkage study associating 1q32 with DR, 75 re-iterating the importance of this region. It is particularly interesting that neither GWAS investigating the retinopathy in type 1 and 2 DM found overlapping regions.…”

Adherence to diabetic eye examination guidelines in Australia: the National Eye Health Survey

“…A number of studies have performed genome-wide linkage analysis in sibships, with inconsistent findings 321;322 . One study found evidence of linkage on chromosome 1p 321 , and another (in Pima Indians) found linkage on chromosomes 3 and 9 323 . To date, the majority of candidate genes studied have exhibited only a weak or no association with DR.…”

Novel Genetic Actors of Diabetes-Associated Microvascular Complications: Retinopathy, Kidney Disease and Neuropathy

“…Interestingly, there is a higher concordance of DR in T2D monozygotic twins (95%) than in T1D monozygotic twins (68%), suggesting that in T1D the initiation and development of its complications are less dependent on genetic factors than in T2D [11]. Additional family studies have shown that, depending on the DR phenotype and the ethnic population examined, siblings and relatives of diabetic patients with DR have approximately a 2-to 4-fold risk of developing the complication compared with relatives of diabetic patients without DR complication [5,[13][14][15][16][17][18]. The degree of familial aggregation is greater for more severe forms of retinopathy.…”

“…A subsequent genome-wide linkage analysis in this population found stronger evidence for linkage on chromosome 1p with LOD scores of 2.58 and 3.1 for single-point and multipoint analyses, respectively [14]. Another genomewide linkage scan for genes contributing to DR, using 794 diabetes participants from 393 MexicanAmerican families in Starr County, Texas, having at least two diabetic siblings, revealed only suggestive evidence of linkage with retinopathy on chromosomes 3 and 12 [20].…”

“…The degree of familial aggregation is greater for more severe forms of retinopathy. Heritability has been estimated to be as high as 27% for DR and 52% for proliferative diabetic retinopathy (PDR), a more advanced form of the disease [13,14].…”