A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes

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 Tregouet; Alexander P. Maxwell; Su Chi Lim; Ronald C.W. Ma; E. Shyong Tai; Shiro Maeda; Valeriya Lyssenko; Tiinamaija Tuomi; Andrzej S. 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

A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes

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 PericoMaria 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 Tregouet, Alexander P. Maxwell, Su Chi Lim, Ronald C.W. Ma, E. Shyong Tai, Shiro Maeda, Valeriya Lyssenko, Tiinamaija Tuomi, Andrzej S. 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

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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
Journal	Diabetes
Volume	67
Issue number	7
Publication status	Published - 2018

All Science Journal Classification (ASJC) codes

Internal Medicine
Endocrinology, Diabetes and Metabolism

UN SDGs

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

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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., Perna, A., Rurali, E., Marcovecchio, M. L., Igo, R. P., Salem, R. M., ... McCarthy, M. I. (2018). A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes. Diabetes, 67(7).

@article{e06d096b5b224614ad55d3c05c6a35d9,

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.",

author = "{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 Schulz, {Christina Alexandra} 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 Tregouet 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 Krolewski, {Andrzej S.} 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 Groop, {Per Henrik} and Colhoun, {Helen M.} and Groop, {Leif C.} and McCarthy, {Mark I.}",

year = "2018",

language = "English",

volume = "67",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "7",

}

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, CA, Orho-Melander, M, Linneberg, A, Christensen, C, Witte, DR, Grarup, N, Brandslund, I, Melander, O, Paterson, AD, Tregouet, D, Maxwell, AP, Lim, SC, Ma, RCW, Tai, ES, Maeda, S, Lyssenko, V, Tuomi, T, Krolewski, AS, Rich, SS, Hirschhorn, JN, Florez, JC, Dunger, D, Pedersen, O, Hansen, T, Rossing, P, Remuzzi, G, Brosnan, MJ, Palmer, CNA, Groop, PH, 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.

TY - JOUR

T1 - A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes

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 - Tregouet, David

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 S.

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

Y1 - 2018

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.

UR - http://www.scopus.com/inward/record.url?scp=85048828771&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048828771&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:85048828771

SN - 0012-1797

VL - 67

JO - Diabetes

JF - Diabetes

IS - 7

ER -

A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

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