A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Finnish Diabetic Nephropathy Study (FinnDiane); Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group; GENIE (GEnetics of Nephropathy an International Effort) Consortium; Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group; Natalie R. Van Zuydam; Emma Ahlqvist; Niina Sandholm; Harshal Deshmukh; N. William Rayner; Moustafa Abdalla; Claes Ladenvall; Daniel Ziemek; Eric Fauman; Neil R. Robertson; Paul M. McKeigue; Erkka Valo; Carol Forsblom; Valma Harjutsalo; Annalisa Perna; Erica Rurali; M. Loredana Marcovecchio; Robert P. Igo; Rany M. Salem; Norberto Perico; Maria Lajer; Annemari Käräjämäki; Minako Imamura; Michiaki Kubo; Atsushi Takahashi; Xueling Sim; Jianjun Liu; Rob M. Van Dam; Guozhi Jiang; Claudia H.T. Tam; Andrea O.Y. Luk; Heung Man Lee; Cadmon K.P. Lim; Cheuk Chun Szeto; Wing Yee So; Juliana C.N. Chan; Su Fen Ang; Rajkumar Dorajoo; Ling Wang; Tan Si Hua Clara; Amy Jayne McKnight; Seamus Duffy; Marcus G. Pezzolesi; Michel Marre; Beata Gyorgy; Samy Hadjadj; Linda T. Hiraki; Tarunveer S. Ahluwalia; Peter Almgren; Christina-Alexandra Schulz; Marju Orho-Melander; Allan Linneberg; Cramer Christensen; Daniel R. Witte; Niels Grarup; Ivan Brandslund; Olle Melander; Andrew D. Paterson; David-Alexandre Trégouët; Alexander P. Maxwell; Su Chi Lim; Ronald C. W. Ma; E. Shyong Tai; Shiro Maeda; Valeriya Lyssenko; Tiinamaija Tuomi; Andrzej Krolewski; Stephen S. Rich; Joel N. Hirschhorn; Jose C. Florez; David Dunger; Oluf Pedersen; Torben Hansen; Peter Rossing; Giuseppe Remuzzi; Mary Julia Brosnan; Colin N.A. Palmer; Per-Henrik Groop; Helen M. Colhoun; Leif C. Groop; Mark I. McCarthy

doi:10.2337/db17-0914

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Finnish Diabetic Nephropathy Study (FinnDiane), Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group, , GENIE (GEnetics of Nephropathy an International Effort) Consortium, Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group, Natalie R. Van Zuydam (Lead / Corresponding author), Emma Ahlqvist, Niina Sandholm, Harshal Deshmukh, N. William Rayner, Moustafa Abdalla, Claes Ladenvall, Daniel Ziemek, Eric Fauman, Neil R. Robertson, Paul M. McKeigue, Erkka Valo, Carol Forsblom, Valma Harjutsalo, Annalisa PernaErica Rurali, M. Loredana Marcovecchio, Robert P. Igo, Rany M. Salem, Norberto Perico, Maria Lajer, Annemari Käräjämäki, Minako Imamura, Michiaki Kubo, Atsushi Takahashi, Xueling Sim, Jianjun Liu, Rob M. Van Dam, Guozhi Jiang, Claudia H.T. Tam, Andrea O.Y. Luk, Heung Man Lee, Cadmon K.P. Lim, Cheuk Chun Szeto, Wing Yee So, Juliana C.N. Chan, Su Fen Ang, Rajkumar Dorajoo, Ling Wang, Tan Si Hua Clara, Amy Jayne McKnight, Seamus Duffy, Marcus G. Pezzolesi, Michel Marre, Beata Gyorgy, Samy Hadjadj, Linda T. Hiraki, Tarunveer S. Ahluwalia, Peter Almgren, Christina-Alexandra Schulz, Marju Orho-Melander, Allan Linneberg, Cramer Christensen, Daniel R. Witte, Niels Grarup, Ivan Brandslund, Olle Melander, Andrew D. Paterson, David-Alexandre Trégouët, Alexander P. Maxwell, Su Chi Lim, Ronald C. W. Ma, E. Shyong Tai, Shiro Maeda, Valeriya Lyssenko, Tiinamaija Tuomi, Andrzej Krolewski, Stephen S. Rich, Joel N. Hirschhorn, Jose C. Florez, David Dunger, Oluf Pedersen, Torben Hansen, Peter Rossing, Giuseppe Remuzzi, Mary Julia Brosnan, Colin N.A. Palmer, Per-Henrik Groop, Helen M. Colhoun, Leif C. Groop, Mark I. McCarthy

Research output: Contribution to journal › Article › peer-review

114 Citations (Scopus)

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Abstract

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined (T1D+T2D) GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 diabetic subjects (and 18,582 DKD cases). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, p=4.5×10-8) associated with 'microalbuminuria' in European T2D cases. However, no replication of this signal was observed in Asian subjects with T2D, or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously-reported DKD signals, except for those at UMOD and PRKAG2, both associated with 'EGFR'. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk-variant discovery for DKD.

Original language	English
Pages (from-to)	1414-1427
Number of pages	14
Journal	Diabetes
Volume	67
Issue number	7
Early online date	27 Apr 2018
DOIs	https://doi.org/10.2337/db17-0914
Publication status	Published - Jul 2018

Keywords

diabetes
kidney
genetic
association
nephropathy
SNP

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/db17-0914Licence: Other

Author Accepted Manuscript
This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http://diabetes.diabetesjournals.org.
Accepted author manuscript, 3.3 MB

Cite this

Finnish Diabetic Nephropathy Study (FinnDiane), Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group, GENIE (GEnetics of Nephropathy an International Effort) Consortium, Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group, Van Zuydam, N. R., Ahlqvist, E., Sandholm, N., Deshmukh, H., Rayner, N. W., Abdalla, M., Ladenvall, C., Ziemek, D., Fauman, E., Robertson, N. R., McKeigue, P. M., Valo, E., Forsblom, C., Harjutsalo, V., ... McCarthy, M. I. (2018). A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes. Diabetes, 67(7), 1414-1427. Advance online publication. https://doi.org/10.2337/db17-0914

@article{a0dae0e947e24a70ba566e75d2022726,

title = "A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes",

abstract = "Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined (T1D+T2D) GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 diabetic subjects (and 18,582 DKD cases). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, p=4.5×10-8) associated with 'microalbuminuria' in European T2D cases. However, no replication of this signal was observed in Asian subjects with T2D, or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously-reported DKD signals, except for those at UMOD and PRKAG2, both associated with 'EGFR'. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk-variant discovery for DKD.",

keywords = "diabetes, kidney, genetic, association, nephropathy, SNP",

author = "{Finnish Diabetic Nephropathy Study (FinnDiane)} and {Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group} and {GENIE (GEnetics of Nephropathy an International Effort) Consortium} and {Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group} and {Van Zuydam}, {Natalie R.} and Emma Ahlqvist and Niina Sandholm and Harshal Deshmukh and Rayner, {N. William} and Moustafa Abdalla and Claes Ladenvall and Daniel Ziemek and Eric Fauman and Robertson, {Neil R.} and McKeigue, {Paul M.} and Erkka Valo and Carol Forsblom and Valma Harjutsalo and Annalisa Perna and Erica Rurali and Marcovecchio, {M. Loredana} and Igo, {Robert P.} and Salem, {Rany M.} and Norberto Perico and Maria Lajer and Annemari K{\"a}r{\"a}j{\"a}m{\"a}ki and Minako Imamura and Michiaki Kubo and Atsushi Takahashi and Xueling Sim and Jianjun Liu and {Van Dam}, {Rob M.} and Guozhi Jiang and Tam, {Claudia H.T.} and Luk, {Andrea O.Y.} and Lee, {Heung Man} and Lim, {Cadmon K.P.} and Szeto, {Cheuk Chun} and So, {Wing Yee} and Chan, {Juliana C.N.} and Ang, {Su Fen} and Rajkumar Dorajoo and Ling Wang and Clara, {Tan Si Hua} and McKnight, {Amy Jayne} and Seamus Duffy and Pezzolesi, {Marcus G.} and Michel Marre and Beata Gyorgy and Samy Hadjadj and Hiraki, {Linda T.} and Ahluwalia, {Tarunveer S.} and Peter Almgren and Christina-Alexandra Schulz and Marju Orho-Melander and Allan Linneberg and Cramer Christensen and Witte, {Daniel R.} and Niels Grarup and Ivan Brandslund and Olle Melander and Paterson, {Andrew D.} and David-Alexandre Tr{\'e}gou{\"e}t and Maxwell, {Alexander P.} and Lim, {Su Chi} and Ma, {Ronald C. W.} and Tai, {E. Shyong} and Shiro Maeda and Valeriya Lyssenko and Tiinamaija Tuomi and Andrzej Krolewski and Rich, {Stephen S.} and Hirschhorn, {Joel N.} and Florez, {Jose C.} and David Dunger and Oluf Pedersen and Torben Hansen and Peter Rossing and Giuseppe Remuzzi and Brosnan, {Mary Julia} and Palmer, {Colin N.A.} and Per-Henrik Groop and Colhoun, {Helen M.} and Groop, {Leif C.} and McCarthy, {Mark I.}",

note = "{\textcopyright} 2018 by the American Diabetes Association.",

year = "2018",

month = jul,

doi = "10.2337/db17-0914",

language = "English",

volume = "67",

pages = "1414--1427",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "7",

}

Finnish Diabetic Nephropathy Study (FinnDiane), Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group, GENIE (GEnetics of Nephropathy an International Effort) Consortium, Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group, Van Zuydam, NR, Ahlqvist, E, Sandholm, N, Deshmukh, H, Rayner, NW, Abdalla, M, Ladenvall, C, Ziemek, D, Fauman, E, Robertson, NR, McKeigue, PM, Valo, E, Forsblom, C, Harjutsalo, V, Perna, A, Rurali, E, Marcovecchio, ML, Igo, RP, Salem, RM, Perico, N, Lajer, M, Käräjämäki, A, Imamura, M, Kubo, M, Takahashi, A, Sim, X, Liu, J, Van Dam, RM, Jiang, G, Tam, CHT, Luk, AOY, Lee, HM, Lim, CKP, Szeto, CC, So, WY, Chan, JCN, Ang, SF, Dorajoo, R, Wang, L, Clara, TSH, McKnight, AJ, Duffy, S, Pezzolesi, MG, Marre, M, Gyorgy, B, Hadjadj, S, Hiraki, LT, Ahluwalia, TS, Almgren, P, Schulz, C-A, Orho-Melander, M, Linneberg, A, Christensen, C, Witte, DR, Grarup, N, Brandslund, I, Melander, O, Paterson, AD, Trégouët, D-A, Maxwell, AP, Lim, SC, Ma, RCW, Tai, ES, Maeda, S, Lyssenko, V, Tuomi, T, Krolewski, A, Rich, SS, Hirschhorn, JN, Florez, JC, Dunger, D, Pedersen, O, Hansen, T, Rossing, P, Remuzzi, G, Brosnan, MJ, Palmer, CNA, Groop, P-H, Colhoun, HM & Groop, LC & McCarthy, MI 2018, 'A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes', Diabetes, vol. 67, no. 7, pp. 1414-1427. https://doi.org/10.2337/db17-0914

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes. / Finnish Diabetic Nephropathy Study (FinnDiane); Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group et al.
In: Diabetes, Vol. 67, No. 7, 07.2018, p. 1414-1427.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

AU - Finnish Diabetic Nephropathy Study (FinnDiane)

AU - Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group

AU - GENIE (GEnetics of Nephropathy an International Effort) Consortium

AU - Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group

AU - Van Zuydam, Natalie R.

AU - Ahlqvist, Emma

AU - Sandholm, Niina

AU - Deshmukh, Harshal

AU - Rayner, N. William

AU - Abdalla, Moustafa

AU - Ladenvall, Claes

AU - Ziemek, Daniel

AU - Fauman, Eric

AU - Robertson, Neil R.

AU - McKeigue, Paul M.

AU - Valo, Erkka

AU - Forsblom, Carol

AU - Harjutsalo, Valma

AU - Perna, Annalisa

AU - Rurali, Erica

AU - Marcovecchio, M. Loredana

AU - Igo, Robert P.

AU - Salem, Rany M.

AU - Perico, Norberto

AU - Lajer, Maria

AU - Käräjämäki, Annemari

AU - Imamura, Minako

AU - Kubo, Michiaki

AU - Takahashi, Atsushi

AU - Sim, Xueling

AU - Liu, Jianjun

AU - Van Dam, Rob M.

AU - Jiang, Guozhi

AU - Tam, Claudia H.T.

AU - Luk, Andrea O.Y.

AU - Lee, Heung Man

AU - Lim, Cadmon K.P.

AU - Szeto, Cheuk Chun

AU - So, Wing Yee

AU - Chan, Juliana C.N.

AU - Ang, Su Fen

AU - Dorajoo, Rajkumar

AU - Wang, Ling

AU - Clara, Tan Si Hua

AU - McKnight, Amy Jayne

AU - Duffy, Seamus

AU - Pezzolesi, Marcus G.

AU - Marre, Michel

AU - Gyorgy, Beata

AU - Hadjadj, Samy

AU - Hiraki, Linda T.

AU - Ahluwalia, Tarunveer S.

AU - Almgren, Peter

AU - Schulz, Christina-Alexandra

AU - Orho-Melander, Marju

AU - Linneberg, Allan

AU - Christensen, Cramer

AU - Witte, Daniel R.

AU - Grarup, Niels

AU - Brandslund, Ivan

AU - Melander, Olle

AU - Paterson, Andrew D.

AU - Trégouët, David-Alexandre

AU - Maxwell, Alexander P.

AU - Lim, Su Chi

AU - Ma, Ronald C. W.

AU - Tai, E. Shyong

AU - Maeda, Shiro

AU - Lyssenko, Valeriya

AU - Tuomi, Tiinamaija

AU - Krolewski, Andrzej

AU - Rich, Stephen S.

AU - Hirschhorn, Joel N.

AU - Florez, Jose C.

AU - Dunger, David

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Rossing, Peter

AU - Remuzzi, Giuseppe

AU - Brosnan, Mary Julia

AU - Palmer, Colin N.A.

AU - Groop, Per-Henrik

AU - Colhoun, Helen M.

AU - Groop, Leif C.

AU - McCarthy, Mark I.

PY - 2018/7

Y1 - 2018/7

N2 - Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined (T1D+T2D) GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 diabetic subjects (and 18,582 DKD cases). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, p=4.5×10-8) associated with 'microalbuminuria' in European T2D cases. However, no replication of this signal was observed in Asian subjects with T2D, or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously-reported DKD signals, except for those at UMOD and PRKAG2, both associated with 'EGFR'. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk-variant discovery for DKD.

AB - Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined (T1D+T2D) GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 diabetic subjects (and 18,582 DKD cases). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, p=4.5×10-8) associated with 'microalbuminuria' in European T2D cases. However, no replication of this signal was observed in Asian subjects with T2D, or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously-reported DKD signals, except for those at UMOD and PRKAG2, both associated with 'EGFR'. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk-variant discovery for DKD.

KW - diabetes

KW - kidney

KW - genetic

KW - association

KW - nephropathy

KW - SNP

UR - http://europepmc.org/articles/PMC6014557?fromSearch=singleResult&fromQuery=29703844

U2 - 10.2337/db17-0914

DO - 10.2337/db17-0914

M3 - Article

C2 - 29703844

SN - 0012-1797

VL - 67

SP - 1414

EP - 1427

JO - Diabetes

JF - Diabetes

IS - 7

ER -

Finnish Diabetic Nephropathy Study (FinnDiane), Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group, GENIE (GEnetics of Nephropathy an International Effort) Consortium, Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group, Van Zuydam NR et al. A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes. Diabetes. 2018 Jul;67(7):1414-1427. Epub 2018 Apr 27. doi: 10.2337/db17-0914

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Palmer, Colin

Health Informatics Centre

Cite this

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Profiles

Palmer, Colin

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Health Informatics Centre

Cite this