Integration of targeted metabolomics and transcriptomics identifies deregulation of phosphatidylcholine metabolism in Huntington’s disease peripheral blood samples

Mastrokolias A, Pool R, Mina E, Hettne KM, van Duijn E, van der Mast RC, van Ommen GJ, ‘t Hoen PAC, Prehn C, Adamski J, van Roon-Mom W

Metabolomics (2016) 12:137, July 2016
DOI: 10.1007/s11306-016-1084-8


Introduction: Metabolic changes have been frequently associated with Huntington’s disease (HD). At the same time peripheral blood represents a minimally invasive sampling avenue with little distress to Huntington’s disease patients especially when brain or other tissue samples are difficult to collect. Objectives: We investigated the levels of 163 metabolites in HD patient and control serum samples in order to identify disease related changes. Additionally, we integrated the metabolomics data with our previously published next generation sequencing-based gene expression data from the same patients in order to interconnect the metabolomics changes with transcriptional alterations. Methods: This analysis was performed using targeted metabolomics and flow injection electrospray ionization tandem mass spectrometry in 133 serum samples from 97 Huntington’s disease patients (29 pre-symptomatic and 68 symptomatic) and 36 controls. Results: By comparing HD mutation carriers with controls we identified 3 metabolites significantly changed in HD(serine and threonine and one phosphatidylcholine—PC ae C36:0) and an additional 8 phosphatidylcholines (PC aa C38:6, PC aa C36:0, PC ae C38:0, PC aa C38:0, PC ae C38:6, PC ae C42:0, PC aa C36:5 and PC ae C36:0) that exhibited a significant association with disease severity. Using workflow based exploitation of pathway databases and by integrating our metabolomics data with our gene expression data from the same patients we identified 4 deregulated phosphatidylcholine metabolism related genes (ALDH1B1, MBOAT1, MTRR and PLB1) that showed significant association with the changes in metabolite concentrations. Conclusion: Our results support the notion that phosphatidylcholine metabolism is deregulated in HD blood and that these metabolite alterations are associated with specific gene expression changes.

Lay summary

Metabolic alterations are often found in Huntington’s disease (HD) patients. Blood sampling is the least invasive way to detect them since brain and other tissue samples are difficult to collect. In this study, the researchers analysed the levels of 163 metabolites in blood serum of Huntington’s disease patients and controls to identify metabolic changes related with the disease. They analysed them jointly with the previously published sequencing data from the same patients, to reveal the links between changes in gene expression and metabolism.

The analysis identified alterations of three phosphatidylcholine metabolites in Huntington’s disease and eight additional ones that are associated with the symptom severity. By integrating metabolomics data with gene expression data, the researchers discovered that deregulated levels of four genes related to phosphatidylcholine metabolism (ALDH1B1, MBOAT1, MTRR and PLB1) were associated with altered metabolite concentrations in the blood of the patients.

This study identified the links between metabolic changes in Huntington’s disease and altered gene expression that could underlie them. The study, financially supported by RD-Connect and its partner project NeurOmics, demonstrates how integrating various types of data, such as from sequencing and blood sampling, can help the researchers understand the mechanisms of genetic diseases.


Further info

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