Whole-exome and Whole-genome Sequencing of 1097 Individuals with Type 1 Diabetes Reveals Novel Genes for Diabetic Kidney Disease

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Abstract Background and hypothesis Diabetic kidney disease (DKD) is a severe diabetic complication affecting one third of individuals with type 1 diabetes. Although several genes and common variants have been associated with DKD, much of the predicted inheritance remain unexplained. Here, we performed next-generation sequencing to assess whether low-frequency variants — single or aggregated — contribute to the missing heritability in DKD. Methods We performed whole-exome sequencing (WES) of 498 individuals and whole-genome sequencing (WGS) of 599 individuals with type 1 diabetes. After quality control, we had next-generation sequencing data available for altogether 1064 individuals, of whom 546 had developed either severe albuminuria or end-stage kidney disease, and 528 had retained normal albumin excretion despite a long duration of type 1 diabetes. Single variants and gene aggregate tests were performed separately for WES and WGS data and combined with meta-analysis. Furthermore, we performed genome-wide aggregate analyses on genomic windows (sliding-window), promoters, and enhancers with the WGS data set. Results In single variant meta-analysis, no variant reached genome-wide significance, but a suggestively associated THAP7 rs369250 variant ( P =1.50×10 -5 ) was replicated in the FinnGen general population GWAS data for chronic kidney disease (CKD) and DKD phenotypes. Gene-aggregate meta-analysis identified suggestive evidence ( P <4.0×10 -4 ) at four genes for DKD, of which NAT16 and LTA (TNB-β) replicated in FinnGen. Of the intergenic regions suggestively associated with DKD, the enhancer on chromosome 18q12.3 ( P =3.94×10 -5 ) showed interaction with the METTL4 gene; the lead variant was replicated, and predicted to alter Mafb binding. Conclusions Our sequencing-based meta-analysis revealed multiple genes, variants and regulatory regions suggestively associated with DKD. However, as no variant or gene reached genome-wide significance, further studies are needed to validate the findings. What was known Genetics is an important factor in the development and progression of diabetic kidney disease (DKD) in individuals with type 1 diabetes. Previously identified genetic associations have mostly been common variants as they originated from GWAS studies. Based on inheritance estimates, the current findings only explain a fraction of the predicted disease risk. This study adds Our study with 1097 sequenced individuals with type 1 diabetes is to date one of the largest sequencing studies on DKD in type 1 diabetes. The study reveals several suggestive variants, genes and intergenic regulatory regions associated with DKD. Low-frequency protein-altering variants inside NAT16 and LTA (encoding for TNF-β), and chromosome 18q12.3 enhancer variant linking to METTL4 were also replicated in FinnGen kidney disease phenotypes. Potential impact The results suggest novel genes that may be important for the onset and development of serious DKD in individuals with type 1 diabetes. In addition to revealing novel biological mechanisms leading to DKD, they may reveal novel treatment targets for DKD. However, further validation and functional studies are still needed.

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