Multi-omic Directed Networks Describe Features of Gene Regulation in Aged Brains and Expand the Set of Genes Driving Cognitive Decline

Frontiers in Genetics
Shinya TasakiDavid A Bennett

Abstract

Multiple aspects of molecular regulation, including genetics, epigenetics, and mRNA collectively influence the development of age-related neurologic diseases. Therefore, with the ultimate goal of understanding molecular systems associated with cognitive decline, we infer directed interactions among regulatory elements in the local regulatory vicinity of individual genes based on brain multi-omics data from 413 individuals. These local regulatory networks (LRNs) capture the influences of genetics and epigenetics on gene expression in older adults. LRNs were confirmed through correspondence to known transcription biophysics. To relate LRNs to age-related neurologic diseases, we then incorporate common neuropathologies and measures of cognitive decline into this framework. This step identifies a specific set of largely neuronal genes, such as STAU1 and SEMA3F, predicted to control cognitive decline in older adults. These predictions are validated in separate cohorts by comparison to genetic associations for general cognition. LRNs are shared through www.molecular.network on the Rush Alzheimer's Disease Center Resource Sharing Hub (www.radc.rush.edu).

References

Jun 20, 2003·Journal of Clinical and Experimental Neuropsychology·Robert WilsonDavid Bennett
Jul 29, 2003·Proceedings of the National Academy of Sciences of the United States of America·John D Storey, Robert Tibshirani
Mar 5, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Malgorzata WesierskaAndré A Fenton
Apr 9, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Amar SahayAlex L Kolodkin
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Dec 31, 2005·Nucleic Acids Research·Chris StarkMike Tyers
Sep 19, 2008·Genome Biology·Yong ZhangX Shirley Liu
Jan 19, 2010·Bioinformatics·Heng Li, Richard Durbin
Oct 15, 2010·Nature Biotechnology·Bradley E BernsteinJames A Thomson
Mar 29, 2011·Nature·Jason ErnstBradley E Bernstein
May 3, 2011·Nature Genetics·Christopher J KleinPeter J Dyck
May 7, 2011·Bioinformatics·Arthur LiberzonJill P Mesirov
Nov 8, 2011·Neurobiology of Aging·Philip L De JagerDenis A Evans
Mar 10, 2012·Human Molecular Genetics·Chris WallaceStefan Blankenberg
Apr 5, 2012·Current Alzheimer Research·David A BennettRobert S Wilson
Apr 12, 2012·Bioinformatics·Andrey A Shabalin
Sep 8, 2012·Genome Research·Stephen G LandtMichael Snyder
Oct 16, 2012·Brain : a Journal of Neurology·J A SchneiderD A Bennett
Oct 31, 2012·Annals of Neurology·David A BennettJulie A Schneider
Jun 12, 2013·ELife·Maria Gutierrez-ArcelusEmmanouil T Dermitzakis
Jun 27, 2013·Annals of Neurology·Patricia A BoyleDavid A Bennett
Oct 15, 2013·Cell·Denes HniszRichard A Young
Jul 6, 2014·Small GTPases·Susanne Schmidt, Anne Debant
Jul 16, 2014·Alzheimer's Research & Therapy·Jeffrey L CummingsKate Zhong
Aug 19, 2014·Nature Neuroscience·Philip L De JagerDavid A Bennett
Aug 22, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Galina P DemyanenkoPatricia F Maness
Dec 31, 2014·Nature Genetics·Sebastian Pott, Jason D Lieb
Jan 31, 2015·The New England Journal of Medicine·Francis S Collins, Harold Varmus
Feb 11, 2015·Psychology and Aging·Robert S WilsonDavid A Bennett
Oct 7, 2015·Nucleic Acids Research·Aziz Khan, Xuegong Zhang
Dec 29, 2015·Bioinformatics·Halit OngenOlivier Delaneau
Dec 29, 2015·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Serge GauthierLefkos T Middleton
May 5, 2016·Nucleic Acids Research·Maxim V KuleshovAvi Ma'ayan
Sep 24, 2016·Cell·X Shawn LiuRudolf Jaenisch

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Citations

Jun 5, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Giuseppe LupoRodolfo Negri
Nov 2, 2019·CPT: Pharmacometrics & Systems Pharmacology·Hugo GeertsMary Pelleymounter
Nov 2, 2019·Genes·Enrique Hernández-LemusSoledad Ochoa
Oct 24, 2018·Frontiers in Neuroscience·Shinya TasakiDavid A Bennett
Oct 13, 2020·Frontiers in Cell and Developmental Biology·Amy R DunnCatherine C Kaczorowski
Oct 16, 2021·Epigenetics : Official Journal of the DNA Methylation Society·Kangli WangChunyu Liu

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Methods Mentioned

BETA
histone acetylation
Genotyping
RNAseq
Chip
ChIP-seq
RNA-seq
acetylation
Mapping
transgenic
nucleotide exchange

Software Mentioned

PEER
RSEM
BEAGLE
MatrixEQTL
R
RNAseq
BLUEPRINT
Illumina Genome Studio
FastQTL
edgeR

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