# Exome-Wide Analysis Identifies a Rare EXD3 Missense Variant Associated With Diabetic Kidney Disease

## TL;DR

A rare genetic variant in the EXD3 gene is strongly linked to diabetic kidney disease, suggesting a new target for understanding and treating the condition.

## Contribution

Identifies a novel rare EXD3 missense variant associated with diabetic kidney disease and provides functional evidence for its role in podocyte biology.

## Key findings

- A rare EXD3 missense variant (p.Asp555Asn) is strongly associated with diabetic kidney disease (OR = 8.7, P = 4.5 × 10-9).
- EXD3 knock-down in human podocytes reduces nephrin gene expression, indicating a functional role in podocyte biology.
- Gene-level analyses identified seven DKD-associated genes, including MUC5B, with evidence of replication.

## Abstract

Diabetic kidney disease (DKD) is a major complication of diabetes, with genetic factors contributing to its progression. Although genome-wide association studies (GWAS) have identified common variants, the role of low-frequency and rare coding variants remains underexplored.

We performed exome-wide meta-analysis of up to 10,312 individuals with type 1 diabetes (T1D) genotyped using genome arrays with focused exome content. We included 10 DKD definitions based on albuminuria, estimated glomerular filtration rate (eGFR), or both. We analyzed nonsynonymous variants individually and used gene-level analyses for low-frequency (minor allele frequency [MAF] < 5%) and rare (< 1%) variants. Replication was performed in 10,066 participants with T1D and in UK Biobank participants with type 2 diabetes (T2D). Gene expression was assessed in cultured human podocytes.

In addition to the known COL4A3 variant, a novel rare missense variant in EXD3 (p.Asp555Asn, rs200080727, minor allele frequency [MAF] = 0.4%) was associated with DKD (odds ratio [OR] = 8.7, P = 4.5 × 10-9). The variant was predicted to be deleterious and EXD3 was downregulated in DKD in kidney expression datasets. EXD3 knock-down in a cultured human podocyte cell line reduced nephrin gene expression, suggesting a functional role in podocyte biology. Gene-level analyses identified 7 DKD-associated genes (P < 3.4 × 10−6), including MUC5B, which harbored multiple low-frequency missense variants and with evidence of replication. Replication in UK Biobank supported the association of EXD3 rs200080727 with albuminuria (P = 0.014).

This study identified a rare EXD3 variant with a strong effect on DKD risk in T1D. Functional data support a role for EXD3 in podocyte integrity and DKD pathogenesis. However, further functional investigations are necessary to understand the underlying molecular mechanisms.