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

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.