Human Kidney Alternative Splicing Information Illuminates Cardiovascular-Kidney-Metabolic Syndrome Risk

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Alternative splicing generates multiple transcripts from a single gene, contributing to functional protein diversity. However, short read RNA sequencing often aggregates isoforms, limiting transcript-level resolution. By analyzing splicing variation in 404 human kidney cortical samples across a spectrum of disease severity, we define the splicing landscape of the human kidney in health and disease. To pinpoint likely disease causing events, we performed splicing and expression quantitative trait locus (sQTL and eQTL) analyses and identified 1,948 genes with significant sQTLs. Integration with genome wide association study (GWAS) data for kidney function and cardiovascular kidney metabolic (CKM) syndrome traits revealed 30 splice variants with evidence of shared genetic regulation via Bayesian colocalization and summary based Mendelian randomization. Six genes, including MANBA, CHMP1A, NT5DC2, GSTA1, GSTA2, and MGMT, demonstrated concordant sQTL, eQTL, and protein QTL (pQTL) signals, implicating transcript level regulation as a key mediator of kidney function associated variation. Similarly, multi layer QTL evidence implicated a CLCNK splice variant in blood pressure regulation. To resolve full transcript structures, we applied long read RNA sequencing, identifying novel isoforms and validating short read quantifications. These analyses nominate specific isoforms, including those of MANBA and GSTA2, as candidate mediators of kidney disease risk. Our findings highlight transcript specific genetic regulation in the human kidney and underscore the value of isoform resolved analysis for understanding complex trait biology.

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