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, 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.
N1 - Publisher Copyright:
© 2025
PY - 2025/10
Y1 - 2025/10
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
UR - https://www.scopus.com/pages/publications/105005179204#tab=citedBy
U2 - 10.1681/ASN.0000000718
DO - 10.1681/ASN.0000000718
M3 - Article
C2 - 40323663
AN - SCOPUS:105005179204
SN - 1046-6673
VL - 36
SP - 1939
EP - 1953
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 10
ER -
SDG 3 Good Health and Well-being