AUTHOR=Tasaki Shinya , Gaiteri Chris , Mostafavi Sara , Yu Lei , Wang Yanling , De Jager Philip L. , Bennett David A. 

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

JOURNAL=Frontiers in Genetics

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00294

DOI=10.3389/fgene.2018.00294

ISSN=1664-8021

ABSTRACT=<p>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 <italic>STAU1</italic> and <italic>SEMA3F</italic>, 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 <ext-link ext-link-type="uri" xlink:href="http://www.molecular.network" xmlns:xlink="http://www.w3.org/1999/xlink">www.molecular.network</ext-link> on the Rush Alzheimer’s Disease Center Resource Sharing Hub (<ext-link ext-link-type="uri" xlink:href="http://www.radc.rush.edu" xmlns:xlink="http://www.w3.org/1999/xlink">www.radc.rush.edu</ext-link>).</p>