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

Joanne B Cole^{1

2

3

4

5}, Emma H Dahlström^{6

7

8}, Damian Fermin⁹, Yogesh Gupta¹⁰, Claire Hill¹⁰, Laura J Smyth¹⁰, Hongbo Liu^{11

12

13

14}, Raymond J Kreienkamp^{2

3

4

5}, Marcus G Pezzolesi^{15

16

17

18}, Jing Jing Cao¹⁹, Erkka Valo^{6

7

8}, Wei-Min Chen²⁰, Suna Onengut-Gumuscu²⁰, Stephen S Rich²⁰, Eoin P Brennan²¹, Darrell Andrews²¹, Ciarán Kennedy²¹, Harvest F Gu²², Lars Stechemesser²³, Raimund Weitgasser²⁴, Jelizaveta Sokolovska²⁵, Lina Radzeviciene²⁶, Rasa Verkauskiene²⁶, Nicolae M Panduru^{27

28}, Peter Rossing^{29

30}, Tarunveer S Ahluwalia^{29

31

32}, Gianpaolo Zerbini³³, Michel Marre³⁴, Samy Hadjadj³⁵, Tina Costacou³⁶, Rachel G Miller³⁶, Barbara E Klein³⁷, Kristine E Lee³⁸, Janet K Snell-Bergeon³⁹, Maria Luiza Caramori⁴⁰, Michael Mauer⁴¹, Kerstin Brismar^{42

43}, Petter Bjornstad⁴⁴, Amy J McKnight¹⁰, Gareth McKay¹⁰, Viji Nair⁹, Rany M Salem⁴⁵, Per-Henrik Groop^{6

7

8

46}, Catherine Godson²¹, Katalin Susztak^{11

12

13

14}, Matthias Kretzler⁹, Alexander P Maxwell¹⁰, Andrzej Krolewski⁴⁷, Andrew Paterson¹⁹, Niina Sandholm-Lafferre^{6

7

8}, Jose C Florez^{2

3

4}, Joel N Hirschhorn^{2

5

48}

Affiliations

¹ Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, Colorado.
² Programs in Metabolism and Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
³ Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, Massachusetts.
⁴ Department of Medicine, Harvard Medical School, Boston, Massachusetts.
⁵ Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.
⁶ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
⁷ Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁸ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁹ Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
¹⁰ Centre for Public Health, School of Medicine, Dentistry and Biomedical Science, Royal Victoria Hospital, Queen's University Belfast, Belfast, Northern Ireland.
¹¹ Renal Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
¹² Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania.
¹³ Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁴ Penn-CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁵ Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
¹⁶ Diabetes and Metabolism Center, University of Utah School of Medicine, Salt Lake City, Utah.
¹⁷ Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah.
¹⁸ Department of Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, Utah.
¹⁹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁰ Department of Genome Sciences, University of Virginia, Charlottesville, Virginia.
²¹ Diabetes Complications Research Centre, School of Medicine, UCD Conway Institute, University College Dublin, Dublin, Ireland.
²² School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
²³ Department of Internal Medicine 1, Paracelsus Medical University, Salzburg, Austria.
²⁴ Competence Centre Diabetes, Diakonissen-Wehrle Hospital, Salzburg, Austria.
²⁵ Faculty of Medicine and Life Sciences, University of Latvia, Riga, Latvia.
²⁶ Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunus, Lithuania.
²⁷ Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
²⁸ IMI - Center of Diabetes, Nutrition and Metabolism, Bucharest, Romania.
²⁹ Steno Diabetes Center Copenhagen, Herlev, Denmark.
³⁰ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³¹ Department of Biology, The Bioinformatics Center, University of Copenhagen, Copenhagen, Denmark.
³² Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
³³ Division of Immunology, Transplantation and Infectious Diseases, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milano, Italy.
³⁴ Institut Necker Enfants Malades, Paris, France.
³⁵ Department of Endocrinology, L'institut du thorax, INSERM,CHU Nantes, CNRS, Nantes Université, Nantes, France.
³⁶ Department of Epidemiology, University of Pittsburgh Public Health, Pittsburgh, Pennsylvania.
³⁷ Department of Ophthalmology and Visual Science, University of Wisconsin-Madison, Madison, Wisconsin.
³⁸ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
³⁹ Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado.
⁴⁰ Department of Endocrinology and Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio.
⁴¹ Divisions of Nephrology, Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota.
⁴² Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁴³ Department of Endocrinology, Diabetes, and Metabolism, Karolinska University Hospital, Stockholm, Sweden.
⁴⁴ Division of Metabolism, Endocrinology, and Nutrition, School of Medicine, University of Washington, Seattle, Washington.
⁴⁵ Division of Epidemiology, Department of Family Medicine and Public Health, University of California San Diego, San Diego, California.
⁴⁶ Department of Diabetes, The Alfred Centre, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁴⁷ Section on Genetic and Epidemiology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.
⁴⁸ Department of Genetics, Harvard Medical School, Boston, Massachusetts.

PMID: 40323663
PMCID: PMC12499614 (available on 2026-10-01)
DOI: 10.1681/ASN.0000000718

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

Joanne B Cole et al. J Am Soc Nephrol. 2025.

. 2025 Oct 1;36(10):1939-1953.

doi: 10.1681/ASN.0000000718. Epub 2025 May 5.

Authors

Affiliations

¹ Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, Colorado.
² Programs in Metabolism and Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
³ Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Massachusetts General Hospital, Boston, Massachusetts.
⁴ Department of Medicine, Harvard Medical School, Boston, Massachusetts.
⁵ Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.
⁶ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
⁷ Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁸ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁹ Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
¹⁰ Centre for Public Health, School of Medicine, Dentistry and Biomedical Science, Royal Victoria Hospital, Queen's University Belfast, Belfast, Northern Ireland.
¹¹ Renal Electrolyte and Hypertension Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
¹² Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania.
¹³ Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁴ Penn-CHOP Kidney Innovation Center, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁵ Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah.
¹⁶ Diabetes and Metabolism Center, University of Utah School of Medicine, Salt Lake City, Utah.
¹⁷ Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah.
¹⁸ Department of Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, Utah.
¹⁹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁰ Department of Genome Sciences, University of Virginia, Charlottesville, Virginia.
²¹ Diabetes Complications Research Centre, School of Medicine, UCD Conway Institute, University College Dublin, Dublin, Ireland.
²² School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
²³ Department of Internal Medicine 1, Paracelsus Medical University, Salzburg, Austria.
²⁴ Competence Centre Diabetes, Diakonissen-Wehrle Hospital, Salzburg, Austria.
²⁵ Faculty of Medicine and Life Sciences, University of Latvia, Riga, Latvia.
²⁶ Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunus, Lithuania.
²⁷ Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
²⁸ IMI - Center of Diabetes, Nutrition and Metabolism, Bucharest, Romania.
²⁹ Steno Diabetes Center Copenhagen, Herlev, Denmark.
³⁰ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³¹ Department of Biology, The Bioinformatics Center, University of Copenhagen, Copenhagen, Denmark.
³² Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
³³ Division of Immunology, Transplantation and Infectious Diseases, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milano, Italy.
³⁴ Institut Necker Enfants Malades, Paris, France.
³⁵ Department of Endocrinology, L'institut du thorax, INSERM,CHU Nantes, CNRS, Nantes Université, Nantes, France.
³⁶ Department of Epidemiology, University of Pittsburgh Public Health, Pittsburgh, Pennsylvania.
³⁷ Department of Ophthalmology and Visual Science, University of Wisconsin-Madison, Madison, Wisconsin.
³⁸ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
³⁹ Department of Pediatrics, Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado.
⁴⁰ Department of Endocrinology and Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio.
⁴¹ Divisions of Nephrology, Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota.
⁴² Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁴³ Department of Endocrinology, Diabetes, and Metabolism, Karolinska University Hospital, Stockholm, Sweden.
⁴⁴ Division of Metabolism, Endocrinology, and Nutrition, School of Medicine, University of Washington, Seattle, Washington.
⁴⁵ Division of Epidemiology, Department of Family Medicine and Public Health, University of California San Diego, San Diego, California.
⁴⁶ Department of Diabetes, The Alfred Centre, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁴⁷ Section on Genetic and Epidemiology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.
⁴⁸ Department of Genetics, Harvard Medical School, Boston, Massachusetts.

PMID: 40323663
PMCID: PMC12499614 (available on 2026-10-01)
DOI: 10.1681/ASN.0000000718

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.

Keywords: GFR; diabetic kidney disease; human genetics.

PubMed Disclaimer

Conflict of interest statement

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F210.

References

1. Hussain S, Chand Jamali M, Habib A, Hussain MS, Akhtar M, Najmi AK. Diabetic kidney disease: an overview of prevalence, risk factors, and biomarkers. Clin Epidemiol Glob Health. 2021;9:2–6. doi: 10.1016/j.cegh.2020.05.016 - DOI
1. Gheith O, Farouk N, Nampoory N, Halim MA, Al-Otaibi T. Diabetic kidney disease: world wide difference of prevalence and risk factors. J Nephropharmacol. 2016;5(1):49–56. PMID: 28197499 - PMC - PubMed
1. Anders HJ, Huber TB, Isermann B, Schiffer M. CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat Rev Nephrol. 2018;14(6):361–377. doi: 10.1038/s41581-018-0001-y - DOI - PubMed
1. Sandholm N Van Zuydam N Ahlqvist E, et al. The genetic landscape of renal complications in type 1 diabetes. J Am Soc Nephrol. 2017;28(2):557–574. doi: 10.1681/ASN.2016020231 - DOI - PMC - PubMed
1. van Zuydam NR Ahlqvist E Sandholm N, et al. A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes. Diabetes. 2018;67(7):1414–1427. doi: 10.2337/db17-0914 - DOI - PMC - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources
- Wolters Kluwer
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous