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

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

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^*, 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 WeitgasserJelizaveta 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^*

^*Corresponding author for this work

Steno Diabetes Center Copenhagen

2 Citations (Scopus)

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.

Original language	English
Article number	10.1681/ASN.0000000718
Journal	Journal of the American Society of Nephrology : JASN
Volume	36
Issue number	10
Pages (from-to)	1939-1953
Number of pages	15
ISSN	1046-6673
DOIs	https://doi.org/10.1681/ASN.0000000718
Publication status	Published - 1 Oct 2025

Keywords

GFR
diabetic kidney disease
human genetics

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Cole, J. B., Dahlström, E. H., Fermin, D., Gupta, Y., Hill, C., Smyth, L. J., Liu, H., Kreienkamp, R. J., Pezzolesi, M. G., Cao, J. J., Valo, E., Chen, W.-M., Onengut-Gumuscu, S., Rich, S. S., Brennan, E. P., Andrews, D., Kennedy, C., Gu, H. F., Stechemesser, L., ... Hirschhorn, J. N. (2025). Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci. Journal of the American Society of Nephrology : JASN, 36(10), 1939-1953. Article 10.1681/ASN.0000000718. https://doi.org/10.1681/ASN.0000000718

Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci. / Cole, Joanne B; Dahlström, Emma H; Fermin, Damian et al.
In: Journal of the American Society of Nephrology : JASN, Vol. 36, No. 10, 10.1681/ASN.0000000718, 01.10.2025, p. 1939-1953.

Research output: Contribution to journal › Journal article › Research › peer-review

Cole, JB, Dahlström, EH, Fermin, D, Gupta, Y, Hill, C, Smyth, LJ, Liu, H, Kreienkamp, RJ, Pezzolesi, MG, Cao, JJ, Valo, E, Chen, W-M, Onengut-Gumuscu, S, Rich, SS, Brennan, EP, Andrews, D, Kennedy, C, Gu, HF, Stechemesser, L, Weitgasser, R, Sokolovska, J, Radzeviciene, L, Verkauskiene, R, Panduru, NM, Rossing, P , Ahluwalia, TS, Zerbini, G, Marre, M, Hadjadj, S, Costacou, T, Miller, RG, Klein, BE, Lee, KE, Snell-Bergeon, JK, Caramori, ML, Mauer, M, Brismar, K, Bjornstad, P, McKnight, AJ, McKay, G, Nair, V, Salem, RM, Groop, P-H, Godson, C, Susztak, K, Kretzler, M, Maxwell, AP, Krolewski, A, Paterson, A, Sandholm-Lafferre, N, Florez, JC & Hirschhorn, JN 2025, 'Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci', Journal of the American Society of Nephrology : JASN, vol. 36, no. 10, 10.1681/ASN.0000000718, pp. 1939-1953. https://doi.org/10.1681/ASN.0000000718

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

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",

author = "Cole, \{Joanne B\} and Dahlstr{\"o}m, \{Emma H\} and Damian Fermin and Yogesh Gupta and Claire Hill and Smyth, \{Laura J\} and Hongbo Liu and Kreienkamp, \{Raymond J\} and Pezzolesi, \{Marcus G\} and Cao, \{Jing Jing\} and Erkka Valo and Wei-Min Chen and Suna Onengut-Gumuscu and Rich, \{Stephen S\} and Brennan, \{Eoin P\} and Darrell Andrews and Ciar{\'a}n Kennedy and Gu, \{Harvest F\} and Lars Stechemesser and Raimund Weitgasser and Jelizaveta Sokolovska and Lina Radzeviciene and Rasa Verkauskiene and Panduru, \{Nicolae M\} and Peter Rossing and Ahluwalia, \{Tarunveer S\} and Gianpaolo Zerbini and Michel Marre and Samy Hadjadj and Tina Costacou and Miller, \{Rachel G\} and Klein, \{Barbara E\} and Lee, \{Kristine E\} and Snell-Bergeon, \{Janet K\} and Caramori, \{Maria Luiza\} and Michael Mauer and Kerstin Brismar and Petter Bjornstad and McKnight, \{Amy J\} and Gareth McKay and Viji Nair and Salem, \{Rany M\} and Per-Henrik Groop and Catherine Godson and Katalin Susztak and Matthias Kretzler and Maxwell, \{Alexander P\} and Andrzej Krolewski and Andrew Paterson and Niina Sandholm-Lafferre and Florez, \{Jose C\} and Hirschhorn, \{Joel N\}",

note = "Copyright {\textcopyright} 2025 by the American Society of Nephrology.",

year = "2025",

month = oct,

day = "1",

doi = "10.1681/ASN.0000000718",

language = "English",

volume = "36",

pages = "1939--1953",

journal = "Journal of the American Society of Nephrology : JASN",

issn = "1046-6673",

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TY - JOUR

T1 - Genome-Wide Association Study of Quantitative Kidney Function in 52,531 Individuals with Diabetes Identifies Five Diabetes-Specific Loci

AU - Cole, Joanne B

AU - Dahlström, Emma H

AU - Fermin, Damian

AU - Gupta, Yogesh

AU - Hill, Claire

AU - Smyth, Laura J

AU - Liu, Hongbo

AU - Kreienkamp, Raymond J

AU - Pezzolesi, Marcus G

AU - Cao, Jing Jing

AU - Valo, Erkka

AU - Chen, Wei-Min

AU - Onengut-Gumuscu, Suna

AU - Rich, Stephen S

AU - Brennan, Eoin P

AU - Andrews, Darrell

AU - Kennedy, Ciarán

AU - Gu, Harvest F

AU - Stechemesser, Lars

AU - Weitgasser, Raimund

AU - Sokolovska, Jelizaveta

AU - Radzeviciene, Lina

AU - Verkauskiene, Rasa

AU - Panduru, Nicolae M

AU - Rossing, Peter

AU - Ahluwalia, Tarunveer S

AU - Zerbini, Gianpaolo

AU - Marre, Michel

AU - Hadjadj, Samy

AU - Costacou, Tina

AU - Miller, Rachel G

AU - Klein, Barbara E

AU - Lee, Kristine E

AU - Snell-Bergeon, Janet K

AU - Caramori, Maria Luiza

AU - Mauer, Michael

AU - Brismar, Kerstin

AU - Bjornstad, Petter

AU - McKnight, Amy J

AU - McKay, Gareth

AU - Nair, Viji

AU - Salem, Rany M

AU - Groop, Per-Henrik

AU - Godson, Catherine

AU - Susztak, Katalin

AU - Kretzler, Matthias

AU - Maxwell, Alexander P

AU - Krolewski, Andrzej

AU - Paterson, Andrew

AU - Sandholm-Lafferre, Niina

AU - Florez, Jose C

AU - Hirschhorn, Joel N

PY - 2025/10/1

Y1 - 2025/10/1

N2 - 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.

AB - 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.

KW - GFR

KW - diabetic kidney disease

KW - human genetics

UR - https://www.scopus.com/pages/publications/105005179204

U2 - 10.1681/ASN.0000000718

DO - 10.1681/ASN.0000000718

M3 - Journal article

C2 - 40323663

SN - 1046-6673

VL - 36

SP - 1939

EP - 1953

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

IS - 10

M1 - 10.1681/ASN.0000000718

ER -

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

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