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

Background and hypothesisDiabetic 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. MethodsWe 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. ResultsIn single variant meta-analysis, no variant reached genome-wide significance, but a suggestively associated THAP7 rs369250 variant (P=1.50x10-5) 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<4.0x10-4) at four genes for DKD, of which NAT16 and LTA (TNB-{beta}) replicated in FinnGen. Of the intergenic regions suggestively associated with DKD, the enhancer on chromosome 18q12.3 (P=3.94x10-5) showed interaction with the METTL4 gene; the lead variant was replicated, and predicted to alter Mafb binding. ConclusionsOur 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 knownO_LIGenetics is an important factor in the development and progression of diabetic kidney disease (DKD) in individuals with type 1 diabetes. C_LIO_LIPreviously 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. C_LI This study addsO_LIOur study with 1097 sequenced individuals with type 1 diabetes is to date one of the largest sequencing studies on DKD in type 1 diabetes. C_LIO_LIThe 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-{beta}), and chromosome 18q12.3 enhancer variant linking to METTL4 were also replicated in FinnGen kidney disease phenotypes. C_LI Potential impactO_LIThe 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. C_LI