Premium
Integrative functional genomic analysis of intron retention in human and mouse brain with Alzheimer's disease
Author(s) -
Li HongDong,
Funk Cory C.,
McFarland Karen,
Dammer Eric B.,
Allen Mariet,
Carrasquillo Minerva M.,
Levites Yona,
Chakrabarty Paramita,
Burgess Jeremy D.,
Wang Xue,
Dickson Dennis,
Seyfried Nicholas T.,
Duong Duc M.,
Lah James J.,
Younkin Steven G.,
Levey Allan I.,
Omenn Gilbert S.,
ErtekinTaner Nilüfer,
Golde Todd E.,
Price Nathan D.
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12254
Subject(s) - intron , biology , gene , rna splicing , transcriptome , genetics , exon , expression quantitative trait loci , computational biology , genome , disease , gene expression , rna , single nucleotide polymorphism , medicine , genotype , pathology
Intron retention (IR) has been implicated in the pathogenesis of complex diseases such as cancers; its association with Alzheimer's disease (AD) remains unexplored. We performed genome‐wide analysis of IR through integrating genetic, transcriptomic, and proteomic data of AD subjects and mouse models from the Accelerating Medicines Partnership‐Alzheimer's Disease project. We identified 4535 and 4086 IR events in 2173 human and 1736 mouse genes, respectively. Quantitation of IR enabled the identification of differentially expressed genes that conventional exon‐level approaches did not reveal. There were significant correlations of intron expression within innate immune genes, like HMBOX1 , with AD in humans. Peptides with a high probability of translation from intron‐retained mRNAs were identified using mass spectrometry. Further, we established AD‐specific intron expression Quantitative Trait Loci, and identified splicing‐related genes that may regulate IR. Our analysis provides a novel resource for the search for new AD biomarkers and pathological mechanisms.