Multimodal analysis stratifies genetic susceptibility and reveals the pathogenic mechanism of kidney injury in diabetic nephropathy.

The genetic etiology of diabetic nephropathy (DN) is masked by inaccurate phenotyping and ethnic disparities. Here, we conduct a stepwise genome-wide association study (GWAS) in the Chinese Han population, using a precise phenotype of biopsy-proven DN as cases, patients with type 2 diabetes without microvascular complications as controls, and healthy individuals for comparison. Our analysis reveals that the genetic etiology of DN is primarily attributed to an inherent susceptibility to kidney injury. We identify 10 suggestive loci, 5 of which have a high probability of being causal, with a missense variant in TCN2 (p.K77M) as the top candidate. Subsequent multidimensional analyses reveal that genetic variants associated with tubulointerstitial injury are key contributors to the DN predisposition. Furthermore, in vitro and in vivo experiments confirm that TCN2 p.K77M induces mitochondrial dysfunction, exacerbating renal tubular cell damage under high-glucose conditions. Our study elucidates the genetic architecture of biopsy-proven DN and provides a mechanistic rationale for its pathogenesis.