ABSTRACT
Diabetic kidney disease (DKD) is a devastating microvascular complication of both type 1 (T1D)
and type 2 diabetes (T2D). It has been shown to have a heritable component, but prior searches
for the genetic determinants of this condition have had limited success. In the Genetics of
Nephropathy – an International Effort (GENIE) Consortium, a collaboration between Queen’s
University Belfast, University of Dublin, University of Helsinki, University of Michigan, University
of Pennsylvania and the Broad Institute, we have leveraged an ongoing co-funding mechanism
between Ireland, Northern Ireland and the US. This international genomics consortium
enucleated a larger Diabetic Nephropathy Collaborative Research Initiative, which coalesced to
assemble nearly 20,000 samples from participants with T1D, with and without kidney disease.
We performed a genome-wide association study (GWAS) and discovered 16 new signals at
genome-wide significance. The strongest signal centered on a protective missense coding
variant at COL4A3, which encodes an integral component of the glomerular basement
membrane, implicating this aspect of kidney biology in DKD. In this award, we propose to build
on this established infrastructure to undertake the following Specific Aims: (1) to significantly
expand our sample size by including ~150,000 samples with DKD in the context of T2D, thereby
substantially increasing our power to discover shared and distinct risk factors for DKD in T1D
and T2D, and to use computational tools to derive biological insights into DKD pathogenesis; (2)
to generate a genome-wide epigenomic dataset in both peripheral blood and human kidney to
inform the relevance of genetic findings, enable the construction of predictive tools, and infer
causality via Mendelian randomization; and (3) to create an experimental pipeline centered on
animal, cellular and organoid models of DKD to pursue functional validation of promising genetic
findings. This ongoing close collaboration of multidisciplinary and synergistic research groups
should advance our knowledge of the molecular determinants of DKD, identify potential
molecular targets for therapeutics, and facilitate clinical prediction.