Key Points

A multiancestry proteome-wide Mendelian randomization analysis was conducted for IgA nephropathy.The findings from the study would help prioritize new drug targets and drug-repurposing opportunities.

Background

The therapeutic options for IgA nephropathy are rapidly evolving, but early diagnosis and targeted treatment remain challenging. We aimed to identify circulating plasma proteins associated with IgA nephropathy by proteome-wide Mendelian randomization studies across multiple ancestry populations.

Methods

In this study, we applied Mendelian randomization and colocalization analyses to estimate the putative causal effects of 2615 proteins on IgA nephropathy in Europeans and 235 proteins in East Asians. Following two-stage network Mendelian randomization, multitrait colocalization analysis and protein-altering variant annotation were performed to strengthen the reliability of the results. A protein–protein interaction network was constructed to investigate the interactions between the identified proteins and the targets of existing medications.

Results

Putative causal effects of 184 and 13 protein–disease pairs in European and East Asian ancestries were identified, respectively. Two protein–disease pairs showed shared causal effects across them (CFHR1 and FCRL2). Supported by the evidence from colocalization analysis, potential therapeutic targets were prioritized and four drug-repurposing opportunities were suggested. The protein–protein interaction network further provided strong evidence for existing medications and pathways that are known to be therapeutically important.

Conclusions

Our study identified a number of circulating proteins associated with IgA nephropathy and prioritized several potential drug targets that require further investigation.