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

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 - 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 -