Unveiling blood pressure‐associated genes in aortic cells through integrative analysis of GWAS and RNA modification‐associated variants

Abstract

Abstract Background Genome‐wide association studies (GWAS) have identified more than a thousand loci for blood pressure (BP). Functional genes in these loci are cell‐type specific. The aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification‐associated single‐nucleotide polymorphisms (RNAm‐SNPs). Methods Utilizing large‐scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium, we identified associations between RNAm‐SNPs and BP. The association between RNAm‐SNPs, gene expression, and BP were examined. Results A total of 355 RNAm‐SNPs related to m6A, m1A, m5C, m7G, and A‐to‐I modification were associated with BP. The related genes were enriched in the pancreatic secretion pathway and renin secretion pathway. The BP GWAS signals were significantly enriched with m6A‐SNPs, highlighting the potential functional relevance of m6A in physiological processes influencing BP. Notably, m6A‐SNPs in CYP11B1, PDE3B, HDAC7, ACE, SLC4A7, PDE1A, FRK, MTHFR, NPPA, CACNA1D, and HDAC9 were identified. Differential methylation and differential expression of the BP genes in FTO‐overexpression and METTL14‐knockdown vascular smooth muscle cells were detected. RNAm‐SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection (AD) cases and controls. In scRNA‐seq study, we identified ARID5A, HLA‐DPB1, HLA‐DRA, IRF1, LINC01091, MCL1, MLF1, MLXIPL, NAA16, NADK, RERG, SRM, and USP53 as differential expression genes for AD in aortic cells. Conclusion The present study identified RNAm‐SNPs in BP loci and elucidated the associations between the RNAm‐SNPs, gene expression, and BP. The identified BP‐associated genes in aortic cells were associated with AD.

Keywords

• aortic dissection
• blood pressure
• genome‐wide association study
• RNA modification
• single‐cell