| Title: | Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci |
| Journal: | Journal of the American Society of Nephrology |
| Published: | 5 May 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40323663/ |
| DOI: | https://doi.org/10.1681/asn.0000000718 |
Publication 15432
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Abstract
Key Points Comprehensive genome-wide association study of eGFR in diabetes, accounting for diabetes duration, kidney disease, and known modifiers, identified novel genetic effects. Incorporation of various kidney multi-omics data provides supporting evidence for the role of novel genome-wide association study loci in diabetic kidney disease. Background Diabetic kidney disease (DKD) is a serious diabetes complication caused by both environmental and genetic risk factors. Previous genome-wide association studies (GWAS) have identified several loci associated with kidney function and kidney disease in the general population and, to a lesser extent, in diabetes. Methods To uncover the genetic factors driving diabetes-induced kidney function, we conducted a series of GWAS meta-analyses of eGFR in 17,267 individuals with type 1 diabetes and 35,264 with type 2 diabetes (52,531 total), using multiple well-characterized cohorts of type 1 diabetes DKD and data from the UK Biobank and SUrrogate markers for Micro- and Macrovascular hard end points for Innovative diabetes Tools (SUMMIT) consortium. We further accounted for DKD case/control status, diabetes duration and subtype, body mass index, glycated hemoglobin levels, and the relationship between eGFR and albuminuria. Results GWAS identified 13 loci associated with eGFR ( P < 5×10 −8 ), with five loci (candidate genes: HIPK3 , TRIM5 , RORA , ERBB4 , and BCL6 / LPP ) not associated with or were in opposite directions as compared with eGFR in the general population. Four candidate genes ( HIPK3 , BCL6, LPP , and RORA ) demonstrated evidence of differential expression in kidney compartments and cells among subgroups with DKD or diabetes versus controls. Lead single-nucleotide polymorphisms rs8027829 ( RORA ) and rs76300256 ( BCL6/LPP ) were methylation quantitative trait loci in whole blood and kidney tissue, respectively, and rs76300256 and its related CpGs all cluster in a kidney enhancer. Conclusions Our integrated approach identified candidate genes with diabetes-specific effects on kidney function. </p>
52 Authors
- Joanne B. Cole
- Emma H. Dahlström
- Damian Fermin
- Yogesh Gupta
- Claire Hill
- Laura J. Smyth
- Hongbo Liu
- Raymond J. Kreienkamp
- Marcus G. Pezzolesi
- Jing Jing Cao
- Erkka Valo
- Wei-Min Chen
- Suna Onengut-Gumuscu
- Stephen S. Rich
- Eoin P. Brennan
- Darrell Andrews
- Ciarán Kennedy
- Harvest F. Gu
- Lars Stechemesser
- Raimund Weitgasser
- Jelizaveta Sokolovska
- Lina Radzeviciene
- Rasa Verkauskiene
- Nicolae M. Panduru
- Peter Rossing
- Tarunveer S. Ahluwalia
- Gianpaolo Zerbini
- Michel Marre
- Samy Hadjadj
- Tina Costacou
- Rachel G. Miller
- Barbara E. Klein
- Kristine E. Lee
- Janet K. Snell-Bergeon
- Maria Luiza Caramori
- Michael Mauer
- Kerstin Brismar
- Petter Bjornstad
- Amy J. McKnight
- Gareth McKay
- Viji Nair
- Rany M. Salem
- Per-Henrik Groop
- Catherine Godson
- Katalin Susztak
- Matthias Kretzler
- Alexander P. Maxwell
- Andrzej Krolewski
- Andrew Paterson
- Niina Sandholm-Lafferre
- Jose C. Florez
- Joel N. Hirschhorn
1 Application
| Application ID | Title |
|---|---|
| 27892 | Genetic studies of type 2 diabetes, related metabolic traits, and their complications |
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