Exome and Genome Sequencing Reveals Novel Variants for Severe Diabetic Retinopathy in Type 1 Diabetes

Diabetic retinopathy affects a substantial proportion of individuals with diabetes and, if not treated, may lead to acquired visual impairment or even blindness. An improved comprehension of the genetics of diabetic retinopathy (DR) is crucial in understanding the disease mechanisms. We aimed to identify rare and low-frequency variants predisposing to severe DR (SDR) in type 1 diabetes.

Whole exome sequencing (WES) and whole genome sequencing (WGS) were performed for SDR in 1071 individuals with type 1 diabetes from the FinnDiane study (WES n = 490, WGS n = 581), altogether 800 with and 271 without SDR. We analyzed the genome using single variant, gene aggregate, sliding window, and regulatory regions analyses. Replication was sought in the FinnDiane genome-wide genotyping data and the UK Biobank summary statistics for WES.

The strongest association in the WGS data was found for an intergenic variant rs9940767 near the IRF8 gene (P = 5.7 × 10-7), while the meta-analysis of WES and WGS found a 3' untranslated region variant rs1239218274 on ZNF367 (P = 2.31 × 10-6). Gene aggregate analysis results were enriched for genes expressed in the retina and identified seven genes with suggestive association with SDR (P < 1 × 10-4), with evidence of replication for AFAP1L1, SLC30A9, HPS3, and PELI1. Sliding window analyses revealed a significant association between SDR and the CSMD2 gene (P = 6.84 × 10-8). In aggregate analyses for regulatory regions, the strongest association was found for the PCBP4 gene promoter (P = 1.22 × 10-5).

This study suggests rare and low-frequency variants and genes associated with SDR in type 1 diabetes, in particular AFAP1L1, SLC30A9, HPS3, PELI1, and CSMD2. However, further validation is required to confirm their roles and mechanisms.