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 -
