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

Research output: Contribution to journalArticle

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 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.

Details

Authors
Organisations
External organisations
  • University of Oxford
  • University of Bergen
  • University of Helsinki
  • Folkhälsan Research Center
  • Helsinki University Central Hospital
  • Institute for Molecular Medicine Finland (FIMM)
  • NIHR Biomedical Research Centre, Oxford
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Endocrinology and Diabetes

Keywords

  • Adult, Aged, Aged, 80 and over, Case-Control Studies, Diabetes Mellitus, Type 2/complications, Diabetic Nephropathies/epidemiology, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Failure, Chronic/complications, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic/complications
Original languageEnglish
Pages (from-to)1414-1427
JournalDiabetes
Volume67
Issue number7
Publication statusPublished - 2018 Jul
Publication categoryResearch
Peer-reviewedYes