Multi-omics predicts risk factors for kidney disease associated with RNA modification

Abstract Background More and more evidence suggests that RNA modification play significant roles in kidney and may be ideal targets of kidney diseases. However, the specific mechanisms of RNA modification in the pathogenesis of kidney diseases remain unclear. Genome-wide association study (GWAS) have identified lots of genetic loci for kidney function and RNA modification. The identification and exploration of the functions of kidney function associated with RNAm-SNPs can help us to explore comprehensive understanding of the underlying mechanism of kidney disease and find potential therapeutic targets. Methods First, we examined the association of RNAm-SNPs with kidney function. Secondly, we performed eQTL and pQTL analyses to explore the function of these identified RNAm-SNPs. Finally, we evaluated the causality between RNAm-SNPs associated gene expression and circulating protein and kidney function by using mendelian randomization analysis and Bayesian colocalization test (coloc). Results 370 RNAm-SNPs related to m6A, m1A, A-to-I, m5C, m7G and m5U modifications were identified. All of them was significantly associated with kidney function. Most of these RNAm-SNPs (60.27%) showed cis-eQTL effects in kidney tissues or in blood cells, while 78 RNAm-SNPs (21.08%) showed cis-pQTL effects in plasma. In addition, we demonstrate a causal association of some RNAm-SNPs associated gene expression and circulating protein with the risk for kidney function. Notably, we demonstrate a causal association of the gene expression in blood and plasma protein of ITIH4 with the risk for kidney function. Conclusions The study found the associations between RNAm-SNPs and kidney function. These SNPs can regulate gene expression and protein levels by RNA modification, eventually leading to kidney dysfunction. Our study provided direct evidences that connect the genetic risk of kidney disease to RNA modification and the new idea for potential therapeutic targets of prevention and treatment of kidney disease.