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

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.

Figure 1

Eight DKD phenotypes were analyzed in subjects with T2D (blue boxes) and in a combined (green boxes) analysis of subjects with T2D or T1D (yellow box). N indicates the total sample count for either the all DKD (number of case subjects is given in parentheses) or the eGFR phenotype and may vary by variant as well as by DKD phenotype. Replication was sought for 164 loci and 47 loci from each analysis, respectively, in subjects of European and Asian ancestry with either T1D or T2D.

Figure 2

A: Manhattan plot of P values from the meta-analysis of allelic effects on early DKD in subjects with T2D of European descent. The red line represents genome-wide significance (P < 5 × 10⁻⁸) and the blue line suggestive significance (P < 1 × 10⁻⁶). The peak represented by rs9942471 (P = 4.5 × 10⁻⁸) near GABRR1 is highlighted in orange. B: A forest plot of allelic OR and imputation information scores (RSQ) from individual studies that contributed to the discovery and replication analyses of rs9942471 in microalbuminuria phenotype; rs9942471 genotypes were not available in Steno. C: A LocusZoom plot of the signal near GABRR1 led by rs9942471 that was associated with microalbuminuria in European subjects with T2D.

Figure 3

A heat map of GRS associations with DKD phenotypes in subjects with either T1D or T2D. A GRS for BMI was significant after correction for multiple testing, whereas other traits, including systolic blood pressure, were not associated with DKD phenotypes. adj., adjusted; FG, fasting glucose; In, insulin; IR, insulin resistance.