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; Maria Lajer; Tarunveer S. Ahluwalia; Allan Linneberg; Daniel R. Witte; Niels Grarup; Oluf Pedersen; Torben Hansen; Peter Rossing; SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium

doi:10.2337/db17-0914

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, Maria Lajer, Tarunveer S. AhluwaliaAllan Linneberg, Daniel R. Witte, Niels Grarup, Oluf Pedersen, Torben Hansen, Peter Rossing, SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium

^*Corresponding author for this work

Department of Clinical Medicine

53 Citations (Scopus)

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
Pages (from-to)	1414-1427
Number of pages	14
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db17-0914
Publication status	Published - 2018

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Van Zuydam, N. R., Ahlqvist, E., Sandholm, N., Deshmukh, H., William Rayner, N., Abdalla, M., Ladenvall, C., Ziemek, D., Fauman, E., Robertson, N. R., McKeigue, P. M., Valo, E., Forsblom, C., Harjutsalo, V., Perna, A., Rurali, E., Loredana Marcovecchio, M., Igo, R. P., Lajer, M., ... SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium (2018). A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes. Diabetes, 67(7), 1414-1427. https://doi.org/10.2337/db17-0914

Van Zuydam, NR, Ahlqvist, E, Sandholm, N, Deshmukh, H, William Rayner, N, Abdalla, M, Ladenvall, C, Ziemek, D, Fauman, E, Robertson, NR, McKeigue, PM, Valo, E, Forsblom, C, Harjutsalo, V, Perna, A, Rurali, E, Loredana Marcovecchio, M, Igo, RP, Lajer, M, Ahluwalia, TS , Linneberg, A, Witte, DR, Grarup, N , Pedersen, O , Hansen, T , Rossing, P & SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium 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

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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 {William Rayner}, N. 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 {Loredana Marcovecchio}, M. and Igo, {Robert P.} and Maria Lajer and Ahluwalia, {Tarunveer S.} and Allan Linneberg and Witte, {Daniel R.} and Niels Grarup and Oluf Pedersen and Torben Hansen and Peter Rossing and {SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium}",

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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 - William Rayner, N.

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 - Loredana Marcovecchio, M.

AU - Igo, Robert P.

AU - Lajer, Maria

AU - Ahluwalia, Tarunveer S.

AU - Linneberg, Allan

AU - Witte, Daniel R.

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Rossing, Peter

AU - SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium

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.

U2 - 10.2337/db17-0914

DO - 10.2337/db17-0914

M3 - Journal article

AN - SCOPUS:85048828771

SN - 0012-1797

VL - 67

SP - 1414

EP - 1427

JO - Diabetes

JF - Diabetes

IS - 7

ER -

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

Abstract

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