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bioRxiv · 10.1101/695221

Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer’s disease

Morabito, S.·Miyoshi, E.·Michael, N.·Swarup, V.
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Abstract

Alzheimers 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 approach across multiple cohorts of human AD, encompassing different brain regions, and integrate with multi-scale datasets comprising of DNA methylation, histone acetylation, transcriptome- and genome-wide association studies as well as quantitative trait loci to define 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 further integrate co-expression modules with single-cell transcriptome generated from 27,321 nuclei from postmortem human brain to identify AD-specific transcriptional changes and assess cell-type proportion changes in the human AD brain. We also show that genetic variants of AD are enriched in a glial AD-associated module and identify key transcription factors regulating co-expressed modules. Additionally, we validate our results in multiple published human AD datasets which are easily accessible using our online resource (https://swaruplab.bio.uci.edu/consensusAD).

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Morabito, S., Miyoshi, E., Michael, N., Swarup, V.. 2019-07-07. Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer’s disease. https://doi.org/10.1101/695221

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