@article{9df991e47ff948cfb450ae1c281a6a50,
title = "Integrative functional genomic analysis of intron retention in human and mouse brain with Alzheimer's disease",
abstract = "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.",
keywords = "Alzheimer's disease, alternative splicing, gene expression, integrative analysis, intron retention",
author = "Li, {Hong Dong} and Funk, {Cory C.} and Karen McFarland and Dammer, {Eric B.} and Mariet Allen and Carrasquillo, {Minerva M.} and Yona Levites and Paramita Chakrabarty and Burgess, {Jeremy D.} and Xue Wang and Dennis Dickson and Seyfried, {Nicholas T.} and Duong, {Duc M.} and Lah, {James J.} and Younkin, {Steven G.} and Levey, {Allan I.} and Omenn, {Gilbert S.} and Nil{\"u}fer Ertekin-Taner and Golde, {Todd E.} and Price, {Nathan D.}",
note = "Funding Information: This work was supported by National Institute on Aging (AG046139‐01 to TEG, NET, NP, SGY, AG051504 to N.E.T); National Institute of Neurological Disorders and Stroke (R01 NS080820 to N.E.T.); the Accelerating Medicine Partnership for AD (U01AG046161); the Emory Alzheimer's Disease Research Center (P50 AG025688); National Institutes of Health grants (P30ES017885‐01A1 and U24CA210967 to GSO); and National Natural Science Foundation of China (61702556 to HDL). Funding Information: AMP-AD University of Florida/Mayo Clinic/Institute for Systems Biology: For the human brain donations, we thank all patients and their families, without whom this work would not have been possible. We thank Thomas G. Beach (Banner Sun Health Institute, AZ) for sharing human tissue. This work was supported by National Institute on Aging (AG046139-01 to TEG, NET, NP, SGY, AG051504 to N.E.T); National Institute of Neurological Disorders and Stroke (R01 NS080820 to N.E.T.); the Accelerating Medicine Partnership for AD (U01AG046161); the Emory Alzheimer's Disease Research Center (P50 AG025688); National Institutes of Health grants (P30ES017885-01A1 and U24CA210967 to GSO); and National Natural Science Foundation of China (61702556 to HDL). Study data were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson's Research. Funding Information: Study data were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Ertekin‐Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data include samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05‐901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson's Research. Publisher Copyright: {\textcopyright} 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association",
year = "2021",
month = jun,
doi = "10.1002/alz.12254",
language = "English (US)",
volume = "17",
pages = "984--1004",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "6",
}