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

FINNDIANE Study centres; 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; Genie Consortium; Michel Marre; Beata Gyorgy; Samy Hadjadj; Linda T Hiraki; Tarunveer S Ahluwalia; Helen M Colhoun

doi:10.2337/db17-0914

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

FINNDIANE Study centres, 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 SalemNorberto 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, Genie Consortium, Michel Marre, Beata Gyorgy, Samy Hadjadj, Linda T Hiraki, Tarunveer S Ahluwalia, Helen M Colhoun

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

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
Early online date	27 Apr 2018
DOIs	https://doi.org/10.2337/db17-0914
Publication status	Published - 1 Jul 2018

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Journal Article

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SUMMIT_T2DKD_2018Accepted author manuscript, 3.3 MB

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FINNDIANE Study centres, 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., ... Colhoun, H. M. (2018). A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes. Diabetes . 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.",

keywords = "Journal Article",

author = "{FINNDIANE Study centres} 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 {Hua Clara}, {Tan Si} and Amy-Jayne McKnight and Seamus Duffy and Pezzolesi, {Marcus G} and Genie Consortium and Michel Marre and Beata Gyorgy and Samy Hadjadj and Hiraki, {Linda T} and Ahluwalia, {Tarunveer S} and Colhoun, {Helen M}",

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

year = "2018",

month = jul,

day = "1",

doi = "10.2337/db17-0914",

language = "English",

journal = "Diabetes ",

issn = "0012-1797",

publisher = "AMER DIABETES ASSOC",

}

FINNDIANE Study centres, 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, Hua Clara, TS, McKnight, A-J, Duffy, S, Pezzolesi, MG, Consortium, G, Marre, M, Gyorgy, B, Hadjadj, S, Hiraki, LT, Ahluwalia, TS & Colhoun, HM 2018, 'A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes', Diabetes . https://doi.org/10.2337/db17-0914

TY - JOUR

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

AU - FINNDIANE Study centres

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 - Hua Clara, Tan Si

AU - McKnight, Amy-Jayne

AU - Duffy, Seamus

AU - Pezzolesi, Marcus G

AU - Consortium, Genie

AU - Marre, Michel

AU - Gyorgy, Beata

AU - Hadjadj, Samy

AU - Hiraki, Linda T

AU - Ahluwalia, Tarunveer S

AU - Colhoun, Helen M

PY - 2018/7/1

Y1 - 2018/7/1

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 - Journal Article

U2 - 10.2337/db17-0914

DO - 10.2337/db17-0914

M3 - Article

C2 - 29703844

SN - 0012-1797

JO - Diabetes

JF - Diabetes

ER -

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

Abstract

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