PRISM-xQTL: Pleiotropic Relationships Integrated with System-level Multiomic QTL analysis for causal genes and
Nitesh Enduru1,2, Zhongming Zhao1,3
1Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
Introduction:
Most Alzheimer's disease (AD) risk variants identified by genome-wide association studies (GWAS) reside in noncoding regions, complicating causal interpretation.
Methods:
We developed PRISM-xQTL (Pleiotropic Relationships Integrated with System-level Multiomic QTL), integrating pleiotropy, co-localization, Mendelian randomization, and mediation analyses across multiomic quantitative trait loci (QTLs; expression QTL [eQTL], methylation QTL [meQTL], splicing QTL [sQTL], proteomic [pQTL], single-cell [sc-eQTL]). Seventy pleiotropic single-nucleotide polymorphisms (SNPs) shared between AD and 11 immune disorders were analyzed. AlphaGenome assessed functional regulation, and The Alzheimer's Cell Atlas (TACA) database was used for drug-target relevance of FCER1G.
Results:
Across 54 Genotype-Tissue Expression (GTEx) tissues, 410 SNP-gene-tissue co-localizations were identified. SNP rs4233366 co-localized with eQTL/meQTL signals at FCER1G, whereas TSPAN14, ISYNA1, and ELL showed splicing and single-cell associations. Mendelian randomization and mediation analyses indicated cytosine-phosphate-Guanine (CpG) sites might effect on AD risk mediated through FCER1G. AlphaGenome and TACA validated FCER1G's the regulatory function and therapeutic relevance of FCER1G.
Discussion:
PRISM-xQTL refines causal inference for noncoding risk variants, highlighting immune regulatory mechanisms and prioritizing therapeutic targets in AD.
Highlights:
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.
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