Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements.
Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements.
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DOI：
10.1038/s41467-017-00353-6
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发表时间：
2017-09-20
影响因子：
16.6
通讯作者：
Fraenkel E
中科院分区：
文献类型：
--
作者：
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
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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DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
4.2
作者：
Garcia-Martinez, Juan M.;Perez-Navarro, Esther;Albech, Jordi
通讯作者：
Albech, Jordi
影响因子：
3
作者：
Eden, Eran;Navon, Roy;Yakhini, Zohar
通讯作者：
Yakhini, Zohar
影响因子：
5.8
作者：
Guo, Yuchun;Papachristoudis, Georgios;Mahony, Shaun
通讯作者：
Mahony, Shaun