Title | Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Pirhaji L, Milani P, Dalin S, Wassie BT, Dunn DE, Fenster RJ, Avila-Pacheco J, Greengard P, Clish CB, Heiman M, Lo DC, Fraenkel E |
Journal | Nat Commun |
Volume | 8 |
Issue | 1 |
Pagination | 623 |
Date Published | 2017 09 20 |
ISSN | 2041-1723 |
Keywords | Aldehyde-Lyases, Animals, Case-Control Studies, Cohort Studies, Humans, Huntington Disease, Male, Mice, Neostriatum, Neural Stem Cells, Phenotype |
Abstract | 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. |
DOI | 10.1038/s41467-017-00353-6 |
Alternate Journal | Nat Commun |
PubMed ID | 28931805 |
PubMed Central ID | PMC5606996 |
Grant List | P30 ES002109 / ES / NIEHS NIH HHS / United States R01 GM089903 / GM / NIGMS NIH HHS / United States R01 NS089076 / NS / NINDS NIH HHS / United States R24 090963 / NH / NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:12pm