Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen

Salem, R.; Todd, J. N.; Sandholm, N.; Cole, J. B.; Chen, W.-M.; Andrews, D.; Pezzolesi, M. G.; MCKEIGUE, P. M.; Hiraki, L. T.; Qiu, C.; Nair, V.; Liao, C. D.; Cao, J. J.; Valo, E.; Onengut-Gumuscu, S.; Smiles, A. M.; MCGURNAGHAN, S.; Haukka, J. K.; Harjutsalo, V.; Brennan, E. P.; van Zuydam, N.; Ahlqvist, E.; Doyle, R.; Ahluwalia, T. S.; Lajer, M.; Hughes, M. F.; Park, J.; Skupien, J.; Spiliopoulou, A.; Liu, A.; Menon, R.; Boustany-Kari, C. M.; Kang, H. M.; Nelson, R. G.; Klein, R.; Klein, B. E.; Lee, K. E.; Gao, X.; Mauer, M.; Maeastroni, S.; Caramori, M. L.; de Boer, I. H.; Miller, R. G.; Gu

doi:10.1101/499616

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bioRxiv · 10.1101/499616

Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen

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Abstract

Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology (COLEC11 and DDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.

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Salem, R., Todd, J. N., Sandholm, N., Cole, J. B., Chen, W.-M., Andrews, D., Pezzolesi, M. G., MCKEIGUE, P. M., Hiraki, L. T., Qiu, C., Nair, V., Liao, C. D., Cao, J. J., Valo, E., Onengut-Gumuscu, S., Smiles, A. M., MCGURNAGHAN, S., Haukka, J. K., Harjutsalo, V., Brennan, E. P., van Zuydam, N., Ahlqvist, E., Doyle, R., Ahluwalia, T. S., Lajer, M., Hughes, M. F., Park, J., Skupien, J., Spiliopoulou, A., Liu, A., Menon, R., Boustany-Kari, C. M., Kang, H. M., Nelson, R. G., Klein, R., Klein, B. E., Lee, K. E., Gao, X., Mauer, M., Maeastroni, S., Caramori, M. L., de Boer, I. H., Miller, R. G., Gu. 2018-12-19. Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen. https://doi.org/10.1101/499616

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