Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements.

Nat Commun 2017 09 20;8(1):623. Epub 2017 Sep 20.

Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts, 02139, USA.

The immense and growing repositories of transcriptional data may contain critical insights for developing new therapies. Current approaches to mining these data largely rely on binary classifications of disease vs. control, and are not able to incorporate measures of disease severity. We report an analytical approach to integrate ordinal clinical information with transcriptomics. We apply this method to public data for a large cohort of Huntington's disease patients and controls, identifying and prioritizing phenotype-associated genes. We verify the role of a high-ranked gene in dysregulation of sphingolipid metabolism in the disease and demonstrate that inhibiting the enzyme, sphingosine-1-phosphate lyase 1 (SPL), has neuroprotective effects in Huntington's disease models. Finally, we show that one consequence of inhibiting SPL is intracellular inhibition of histone deacetylases, thus linking our observations in sphingolipid metabolism to a well-characterized Huntington's disease pathway. Our approach is easily applied to any data with ordinal clinical measurements, and may deepen our understanding of disease processes.Identifying gene subsets affecting disease phenotypes from transcriptome data is challenge. Here, the authors develop a method that combines transcriptional data with disease ordinal clinical measurements to discover a sphingolipid metabolism regulator involving in Huntington's disease progression.

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http://dx.doi.org/10.1038/s41467-017-00353-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606996PMC
September 2017
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References

(Supplied by CrossRef)

NF Marko et al.
Sci. Transl. Med 2010

M West et al.
Proc. Natl Acad. Sci. USA 2001

LJ van’t Veer et al.
Nature 2008

JP Magalhães de et al.
Bioinformatics 2009

W Chu et al.
Bioinformatics 2005

LH Sobin et al.
Cancer 1997

CP Hughes et al.
Br. J. Psychiatry 1982

P Sun et al.
PLoS Negl. Trop. Dis 2013

K Eid et al.
J. Orthop. Res. 2006

T Seredenina et al.
Neurobiol. Dis. 2012

A Hodges et al.
Hum. Mol. Genet. 2006

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