Diabetic kidney disease (DKD) is a serious complication of diabetes. Substantial between-patient variation exists in the progression and severity of DKD; however, the factors that contribute to this variability are unknown. Several lines of evidence suggest that underlying genetic components influence the risk of DKD, but few loci identified in genome-wide association studies (GWAS) have been confirmed. New findings from the largest GWAS to date of DKD in patients with type 2 diabetes mellitus (T2DM) highlight the challenges of identifying risk variants associated with DKD. “Sample size is key, and previous results from GWAS of DKD in T2DM and T1DM have been underpowered, with reported signals showing limited replication,” says Mark McCarthy. “We set out to perform a substantially larger study than previous studies, but despite samples sizes that exceeded 40,000, the yield of novel discoveries was modest.”

Given uncertainties over which of the various DKD stages might be the most tractable for genetic dissection, the researchers separated cases into eight phenotypic classes. Using this approach, they identified a novel locus, GABRR1 (centred on rs9942471), associated with microalbuminuria in European individuals with T2DM, which was not present in individuals of Asian ancestry, but they caution the need for replication studies to confirm this association. They could not confirm previously reported genetic associations, except for UMOD and PRKAG, which were associated with estimated glomerular filtration rate. “We did, however, find some evidence that genetic variants influencing insulin action and obesity are also associated with DKD risk, reinforcing evidence of a connection between DKD and these traits from other sources,” says McCarthy.