Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

• DOI: 10.1681/asn.2019030218
• Publication Date: 2019-09-19T22:45:16Z
• Authors: Rany M. Salem; Jennifer N. Todd; Niina Sandholm; Joanne B. Cole; Wei-Min Chen; Darrell Andrews; Marcus G. Pezzolesi; Paul M. McKeigue; Linda T. Hiraki; Chengxiang Qiu; Viji Nair; Chen Di Liao; Jing Jing Cao; Erkka Valo; Suna Onengut-Gumuscu; Adam M. Smiles; Stuart J. McGurna...; Jani K. Haukka; Valma Harjutsalo; Eoin P. Brennan; Natalie van Zuydam; Emma Ahlqvist; Ross Doyle; Tarunveer S. Ahlu...; Maria Lajer; Maria F. Hughes; Jihwan Park; Jan Skupien; Athina Spiliopoulou; Andrew Liu; Rajasree Menon; Carine M. Boustan...; Hyun M. Kang; Robert G. Nelson; Ronald Klein; Barbara E. Klein; Kristine E. Lee; Xiaoyu Gao; Michael Mauer; Silvia Maestroni; Maria Luiza Caramori; Ian H. de Boer; Rachel G. Miller; Jingchuan Guo; Andrew P. Boright; David Tregouet; Beata Gyorgy; Janet K. Snell-Be...; David M. Maahs; Shelley B. Bull; Angelo J. Canty; Colin N.A. Palmer; Lars Stechemesser; Bernhard Paulweber; Raimund Weitgasser; Jelizaveta Sokolo...; Vita Rovīte; Valdis Pīrāgs; Edita Prakapiene; Lina Radzeviciene; Rasa Verkauskiene; Nicolae Mircea Pa...; Leif C. Groop; Mark I. McCarthy; Harvest F. Gu; Anna Möllsten; Henrik Falhammar; Kerstin Brismar; Finian Martin; Peter Rossing; Tina Costacou; Gianpaolo Zerbini; Michel Marre; Samy Hadjadj; Amy J. McKnight; Carol Forsblom; Gareth McKay; Catherine Godson; A. Peter Maxwell; Matthias Kretzler; Katalin Susztak; Helen M. Colhoun; Andrzej Krolewski; Andrew D. Paterson; Per-Henrik Groop; Stephen S. Rich; Joel N. Hirschhorn; Jose C. Florez
• Keywords: Genome-wide Association Study; Alport syndrome; Albuminuria; Genetic Association

Significance Statement Although studies show that diabetic kidney disease has a heritable component, searches for the genetic determinants of this complication diabetes have had limited success. In study, new international genomics consortium, JDRF funded Diabetic Nephropathy Collaborative Research Initiative, assembled nearly 20,000 samples from participants with type 1 diabetes, and without disease. The authors found 16 disease–associated loci at genome-wide significance. strongest signal centers on protective missense coding variant COL4A3 , gene encodes component glomerular basement membrane that, when mutated, causes progressive inherited nephropathy Alport syndrome. These GWAS-identified risk may provide insights into pathogenesis help identify potential biologic targets prevention treatment. Background demonstrates both familial clustering single nucleotide polymorphism heritability, specific factors influencing remain largely unknown. Methods To variants predisposing to disease, we performed association study (GWAS) analyses. Through collaboration Diabetes large collection cohorts harmonized phenotypes. We used spectrum ten definitions based albuminuria renal function. Results Our GWAS meta-analysis included results up 19,406 individuals European descent diabetes. identified significant loci. (rs55703767) is common mutation in collagen IV alpha 3 chain ( COL4A3) gene, which major structural (GBM). Mutations are implicated nephropathies, including rs55703767 minor allele (Asp326Tyr) against several ESKD, demonstrated GBM width; carriers thinner before any signs its effect was dependent glycemia. Three other or near genes known suggestive involvement condition BMP7) biology COLEC11 DDR1 ). Conclusions novel