Faculty, Staff and Student Publications

Language

English

Publication Date

2-1-2026

Journal

Alzheimer's & Dementia

DOI

10.1002/alz.71073

PMID

41611629

PMCID

PMC12854938

PubMedCentral® Posted Date

1-29-2026

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Quantitative Trait Loci, Humans, Alzheimer Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Pleiotropy, Genetic Predisposition to Disease, Mendelian Randomization Analysis, Genotype, colocalization, FCER1G, Mendelian randomization, pleiotropy, quantitative trait loci, single‐cell gene expression

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