A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.
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., Almgren P., Schulz C-A., 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 P-H., Colhoun HM., Groop LC., McCarthy MI.
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.