Tham, M. S. | Search bioRxiv

bioRxiv2026

A Cross-Species Systems Genetics Framework Identifies Causal Genes in Diabetic Nephropathy

Diabetic nephropathy (DN) is the leading cause of kidney failure in the developed world, but the genetic architecture of DN susceptibility is not well characterised. Here we apply a systems genetics approach in a mouse model of DN to discover novel QTLs for clinically relevant phenotypes including albuminuria, glomerulosclerosis, and macrophage infiltration. For context and prioritisation, we combined single-cell-transcriptomics-guided pQTL and eQTL mapping with cell-type-specific co-expression networks, identifying 192 candidate pGenes for albuminuria. While many were novel, 27% had prior genetic associations, and 40% were validated in a human diabetic cohort. Twelve genes belong to a podocyte network enriched for human GWAS signals. Among those, functional significance of the E3 ubiquitin ligases DCAF6 and ZNRF2 was confirmed by knockdown in Drosophila nephrocytes. Our systems genetics approach identified DN susceptibility genes previously validated in human GWAS while uncovering potential new genes and pathways that could be exploited for risk stratification and therapeutics development.

systems biology↗

bioRxiv2025

Anks3 mediates cilia dependent polycystin signaling and is essential for adult kidney homeostasis

The existence of a cilia-dependent cyst activation (CDCA) pathway underlying autosomal dominant polycystic kidney disease was identified by showing that cyst progression following loss of polycystins is significantly suppressed by removal of structurally intact cilia. We applied translating ribosome affinity purification RNASeq on pre-cystic mouse kidneys to determine a cell-autonomous in vivo translatome associated with CDCA and identified Glis2 as an early effector of polycystin signaling. Here, to discover additional components of CDCA, we used polycystin-dependent Glis2 expression as a functional readout and identified Anks3, from the CDCA pattern translatome, as a candidate cytosolic regulator of polycystin signaling. Anks3 regulates polycystin-dependent Glis2 expression both in vitro and in vivo. Anks3 also undergoes polycystin-dependent changes in phosphorylation state. Inactivation of Anks3 in Pkd1 mouse models suppresses cyst progression, but also results in rapidly progressive kidney injury independent of polycystins. Anks3 inactivation also normalizes a broader spectrum of polycystin-dependent CDCA translatome changes. These findings define Anks3 as a central regulator of cilia dependent polycystin signaling, functioning downstream of cilia and polycystins and upstream of Glis2, and show that Anks3 has broader functions in maintaining renal structural and functional homeostasis.

genetics↗