Integrative genomic analysis of RNA-modification-single nucleotide polymorphisms associated with kidney function.

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• RNA modifications are increasingly recognized for their role in kidney function and disease pathogenesis.
• The precise mechanisms linking RNA modifications to kidney disease remain largely unexplored.
• Genome-wide association studies (GWAS) have identified genetic loci relevant to both kidney function and RNA modification.

Purpose of the Study:

• To investigate the association between RNA modification-related single-nucleotide polymorphisms (RNAm-SNPs) and estimated glomerular filtration rate (eGFR).
• To explore the functional impact of identified RNAm-SNPs using expression quantitative trait locus (eQTL) and protein quantitative trait locus (pQTL) analyses.
• To evaluate the causal relationship between RNAm-SNP-associated gene expression, protein levels, and kidney function via Mendelian randomization (MR).

Main Methods:

• Association analysis of 252 RNAm-SNPs with eGFR.
• cis-eQTL and cis-pQTL analyses in blood cells and plasma.
• Mendelian randomization (MR) analysis to assess causality.

Main Results:

• 252 RNAm-SNPs associated with various RNA modifications (m 6 A, m 1 A, A-to-I, m 5 C, m 7 G, m 5 U) were identified and all significantly correlated with eGFR.
• Significant cis-eQTL effects were observed in 47.22% of RNAm-SNPs in blood cells, and cis-pQTL effects in 28.57% in plasma.
• A causal association was established between RNAm-SNP-associated gene expression, circulating protein levels, and eGFR decline, with some genes/proteins (e.g., CDK10, SDCCAG8) linked to kidney disease.

Conclusions:

• This study establishes a significant association between RNAm-SNPs and kidney function.
• RNAm-SNPs influence gene and protein expression through RNA modifications, contributing to kidney dysfunction.
• The findings provide novel insights into the genetic basis of kidney disease, linking genetic risk to RNA modification and suggesting potential therapeutic avenues.