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

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. 7; pp. 1414 - 1427
• Main Authors: van Zuydam, Natalie R., Ahlqvist, Emma, Sandholm, Niina, Deshmukh, Harshal, Rayner, N. William, Abdalla, Moustafa, Ladenvall, Claes, Ziemek, Daniel, Fauman, Eric, Robertson, Neil R., McKeigue, Paul M., Valo, Erkka, Forsblom, Carol, Harjutsalo, Valma, Perna, Annalisa, Rurali, Erica, Marcovecchio, M. Loredana, Igo, Robert P., Salem, Rany M., Perico, Norberto, Lajer, Maria, Käräjämäki, Annemari, Imamura, Minako, Kubo, Michiaki, Takahashi, Atsushi, Sim, Xueling, Liu, Jianjun, van Dam, Rob M., Jiang, Guozhi, Tam, Claudia H.T., Luk, Andrea O.Y., Lee, Heung Man, Lim, Cadmon K.P., Szeto, Cheuk Chun, So, Wing Yee, Chan, Juliana C.N., Ang, Su Fen, Dorajoo, Rajkumar, Wang, Ling, Clara, Tan Si Hua, McKnight, Amy-Jayne, Duffy, Seamus, Pezzolesi, Marcus G., Marre, Michel, Gyorgy, Beata, Hadjadj, Samy, Hiraki, Linda T., Ahluwalia, Tarunveer S., Almgren, Peter, Schulz, Christina-Alexandra, Orho-Melander, Marju, Linneberg, Allan, Christensen, Cramer, Witte, Daniel R., Grarup, Niels, Brandslund, Ivan, Melander, Olle, Paterson, Andrew D., Tregouet, David, Maxwell, Alexander P., Lim, Su Chi, Ma, Ronald C.W., Tai, E Shyong, Maeda, Shiro, Lyssenko, Valeriya, Tuomi, Tiinamaija, Krolewski, Andrzej S., Rich, Stephen S., Hirschhorn, Joel N., Florez, Jose C., Dunger, David, Pedersen, Oluf, Hansen, Torben, Rossing, Peter, Remuzzi, Giuseppe, Brosnan, Mary Julia, Palmer, Colin N.A., Groop, Per-Henrik, Colhoun, Helen M., Groop, Leif C., McCarthy, Mark I., Koivula, S., Uggeldahl, T., Forslund, T., Halonen, A., Koistinen, A., Koskiaho, P., Laukkanen, M., Saltevo, J., Tiihonen, M., Forsen, M., Granlund, H., Jonsson, A.-C., Nyroos, B., Kinnunen, P., Orvola, A., Salonen, T., Vähänen, A., Paldanius, Kotka R., Riihelä, M.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2018
• Subjects: Adult; Aged; Aged, 80 and over; Basic Medicine; Case-Control Studies; Clinical Medicine; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - genetics; Diabetic Nephropathies - epidemiology; Diabetic Nephropathies - genetics; Diabetic nephropathy; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Genetic Predisposition to Disease; Genetics/Genomes/Proteomics/Metabolomics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotype & phenotype; Glomerular filtration rate; Humans; Kidney diseases; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - epidemiology; Kidney Failure, Chronic - genetics; Kidneys; Klinisk medicin; Male; Medical and Health Sciences; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Phenotypes; Polymorphism, Single Nucleotide; Quantitative analysis; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - epidemiology; Renal Insufficiency, Chronic - genetics; Replication
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db17-0914

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 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. 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 estimated glomerular filtration rate. 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.