PRISM‐xQTL: Pleiotropic Relationships Integrated with System‐level Multiomic QTL analysis for causal genes and molecular mediators in Alzheimer's disease

We developed PRISM-xQTL (Pleiotropic Relationships Integrated with System-level Multiomic QTL), a multiomic framework integrating pleiotropy, co-localization, Mendelian randomization, and mediation analyses to dissect genetic regulation in Alzheimer's disease (AD) and immune-mediated diseases. Identified 410 single-nucleotide polymorphism (SNP)-gene-tissue co-localizations across 54 Genotype-Tissue Expression (GTEx) tissues, including 28 multi-gene/multi-tissue signals, 35 methylation quantitative trait locus (meQTL) pairs in blood, with rs4233366 and rs479486 overlapping expression QTLs (eQTLs). Multi-trait co-localization, Mendelian randomization and mediation analyses at rs4233366 and rs479486 revealed convergent regulatory effects across genes and tissues. AlphaGenome profiling showed that rs4233366 drives allele-specific transcriptional and splicing regulation at FCER1G, linking immune signaling to AD risk.