Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci

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.

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Journal
Journal of the American Society of Nephrology
Published
2025-05-05
DOI
https://doi.org/10.1681/asn.0000000718
Citations
3
Primary Topic
Birth, Development, and Health
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article
Field-Weighted Citation Impact
10.48

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article

Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci

Michael Mauer, Joel N. Hirschhorn, Jingjing Cao, Kerstin Brismar et al.
3 citations
Journal of the American Society of Nephrology
Birth, Development, and Health
10.48
article

Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci

Michael Mauer, Joel N. Hirschhorn, Jingjing Cao, Kerstin Brismar, Damian Fermin, Maria Luiza Caramori, Viji Nair, Tarunveer S. Ahluwalia, Laura J. Smyth, Per‐Henrik Groop, Harvest F. Gu, Lars Stechemesser, Eoin Brennan, Erkka Valo, Petter Bjornstad, Jeļizaveta Sokolovska, Samy Hadjadj, Raymond J. Kreienkamp, Gianpaolo Zerbini, Emma H. Dahlström, Hongbo Liu, José C. Florez, Yogesh Gupta, Marcus G. Pezzolesi, Lina Radzevičienė, Tina Costacou, Niina Sandholm, Gareth J. McKay, Andrew D. Paterson, Raimund Weitgasser, Katalin Suszták, Janet K. Snell‐Bergeon, Ronald Klein, Joanne B. Cole, Darrell Andrews, Rasa Verkauskienė, Amy Jayne McKnight, Kristine E. Lee, Stephen S. Rich, Matthias Kretzler, Claire Hill, Andrzej S. Królewski, Rany M. Salem, Nicolae Mircea Panduru, Ciarán Kennedy, Peter R Rossing, Michel Marre, Alexander P. Maxwell, Suna Önengüt-Gümüşcü, Catherine Godson, Wei‐Min Chen, Rachel G. Miller
article en
3 citations

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.

Journal of the American Society of NephrologyVol. 36(10)
University College Dublin (IE), Broad Institute (US), University of Copenhagen (DK), Queen's University Belfast (GB), Boston Children's Hospital (US), Joslin Diabetes Center (US), Centre National de la Recherche Scientifique (FR), University of Minnesota (US), Beth Israel Deaconess Medical Center (US), Cleveland Clinic (US), Lithuanian University of Health Sciences (LT), Karolinska University Hospital (SE), University of Helsinki (FI), Steno Diabetes Centers (DK), University of Wisconsin–Madison (US), Harvard University (US), University of Ulster (GB), Vita-Salute San Raffaele University (IT), Inserm (FR), China Pharmaceutical University (CN), Carol Davila University of Medicine and Pharmacy (RO), University of Pittsburgh (US), University of Washington (US), University of Utah (US), University of Michigan (US), Paracelsus Medical University (AT), Helsinki University Hospital (FI), Hospital for Sick Children (CA), The Alfred Hospital (AU), Karolinska Institutet (SE), University of California San Diego (US), Institut Necker Enfants Malades (FR), University of Colorado Health (US), Massachusetts General Hospital (US), Monash Alfred Psychiatry Research centre (AU), Diakonissenkrankenhaus (DE), Penn Center for AIDS Research (US), Royal Victoria Hospital (GB), SickKids Foundation (CA), Institut du Thorax (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Folkhälsans Forskningscentrum (FI), Institute of Nutrition, Metabolism and Diabetes (CA), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), University of Virginia (US), Monash University (AU), University of Pennsylvania (US), University of Latvia (LV), University of Colorado Denver (US), Nantes Université (FR)
American Diabetes Association, American Society of Nephrology, Pfizer, Sanofi, Gilead Sciences, University of Pennsylvania, Regeneron Pharmaceuticals, Wilhelm och Else Stockmanns Stiftelse, UK Research and Innovation, Folkhälsanin Tutkimussäätiö, Department for the Economy, Kidney Research UK, Queen's University Belfast, Science Foundation Ireland, Queen's University, Novo Nordisk, Samfundet Folkhälsan, Sigrid Juséliuksen Säätiö, Novo Nordisk Fonden, National Institutes of Health, Genentech, Perelman School of Medicine, University of Pennsylvania, Medical Research Council, National Heart, Lung, and Blood Institute
Good health and well-being
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Birth, Development, and Health
10.48
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