Alzheimer’s disease (AD) is a devastating neurological disorder characterized by changes in cell-type proportions and consequently marked alterations of the transcriptome. Here we use a data-driven systems biology meta-analytical approach across three human AD cohorts, encompassing six cortical brain regions, and integrate with multi-scale datasets comprising of DNA methylation, histone acetylation, transcriptome- and genome-wide association studies, and quantitative trait loci to further characterize the genetic architecture of AD. We perform co-expression network analysis across more than twelve hundred human brain samples, identifying robust AD-associated dysregulation of the transcriptome, unaltered in normal human aging. We assess the cell-type specificity of AD gene co-expression changes and estimate cell-type proportion changes in human AD by integrating co-expression modules with single-cell transcriptome data generated from 27,321 nuclei from human postmortem prefrontal cortical tissue. We also show that genetic variants of AD are enriched in a microglial AD-associated module and identify key transcription factors regulating co-expressed modules. Additionally, we validate our results in multiple published human AD gene expression datasets, which can be easily accessed using our online resource (https://swaruplab.bio.uci.edu/consensusAD).
Morabito, S., Miyoshi, E., Michael, N. & Swarup, V. Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer’s disease. bioRxiv 695221 (2019). doi:10.1101/695221
ROSMAP PFC (Mostafavi et al; Nat. Neurosci, 2018)
Mayo TC (Allen et al., Sci. Data, 2016)
Mt. Sinai FP, doi: 10.7303/syn2580853
Mt. Sinai IFG, doi: 10.7303/syn2580853
Mt. Sinai PHG, doi: 10.7303/syn2580853
Mt. Sinai STG, doi: 10.7303/syn2580853
HBTRC PFC (Zhang et al., Cell, 2013)
FC Webster et al., Am J Hum Gen, 2009
TC Webster et al., Am J Hum Gen, 2009
SFG Berchtold et al., PNAS, 2008
PCG Berchtold et al., PNAS, 2008
Developed in the Swarup Lab by Sam Morabito .