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bioRxiv · 10.1101/302737

A computational framework identifying concordant gene expression-neuropathology associations reveals Complex I as a potential Alzheimer’s disease therapeutic target

Celik, S.·Russell, J. C.·Mukherjee, S.·Crane, P. K.·Keene, D.·Bobb, J.·Kaeberlein, M.·Lee, S.-I.
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Abstract

Identifying gene expression markers for Alzheimers disease (AD) neuropathology through meta-analysis is a complex undertaking because available data are often from different studies and/or brain regions involving study-specific confounders and/or region-specific biological processes. Here we introduce a novel probabilistic model-based framework, DECODER, leveraging these discrepancies to identify robust biomarkers for complex phenotypes. Our experiments present: (1) DECODERs potential as a general meta-analysis framework widely applicable to various diseases (e.g., AD and cancer) and phenotypes (e.g., Amyloid-{beta} (A{beta}) pathology, tau pathology, and survival), (2) our results from a meta-analysis using 1,746 human brain tissue samples from nine brain regions in three studies -- the largest expression meta-analysis for AD, to our knowledge --, and (3) in vivo validation of identified modifiers of A{beta} toxicity in a transgenic Caenorhabditis elegans model expressing AD-associated A{beta}, which pinpoints mitochondrial Complex I as a critical mediator of proteostasis and a promising pharmacological avenue toward treating AD.

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Celik, S., Russell, J. C., Mukherjee, S., Crane, P. K., Keene, D., Bobb, J., Kaeberlein, M., Lee, S.-I.. 2018-04-17. A computational framework identifying concordant gene expression-neuropathology associations reveals Complex I as a potential Alzheimer’s disease therapeutic target. https://doi.org/10.1101/302737

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