Multi-omics Mendelian randomization and experimental validation identify PRKAB1 as a regulator of phosphatidylcholine metabolism in IBD.
Abstract
Phosphatidylcholines (PCs) are implicated in inflammatory bowel disease (IBD), yet the genetic and pathophysiological mechanisms underlying phosphatidylcholine metabolism in IBD remain poorly characterized. Here, we integrated multi-omics data with Mendelian randomization (MR) and genetic colocalization to dissect causal genetic associations between phosphatidylcholine metabolism-related genes and IBD. We conducted two-sample MR using discovery data from the FinnGen study and replication data from the IBD Genetics Consortium to evaluate causal links across 78 lipid species: 5 lysophosphatidylcholines (lyso-PCs), 46 phosphatidylcholines (PCs), and 27 phosphatidylcholine ethers (PCEs). Summary-data-based MR and multi-omics quantitative trait locus (QTL) analyses covering DNA methylation, gene expression, and protein abundance QTLs identified PRKAB1 as significantly associated with reduced risk of both IBD and ulcerative colitis (UC). Combined analysis of Gene Expression Omnibus (GEO) and single-cell RNA sequencing (scRNA-seq) data revealed marked downregulation of PRKAB1 specifically in colonic epithelial cells during active UC inflammation. Functional loss-of-function validation via PRKAB1 knockdown confirmed its regulatory function, triggering significant reductions in intracellular PC and lyso-PC concentrations. Quantitative real-time PCR (qRT-PCR) further demonstrated that this metabolic shift was accompanied by suppressed expression of core phosphatidylcholine metabolic…
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