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Preliminary Transcriptome Analysis in Lymphoblasts from Cluster Headache and Bipolar Disorder Patients Implicates Dysregulation of Circadian and Serotonergic Genes

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Abstract

Bipolar disorder (BD) and cluster headache (CH) are distinct conditions with important similarities such as a temporal pattern of disturbances, dysregulation of the sleep–wake cycle, and response to lithium treatment in a proportion of patients. Aiming to identify common transcription signatures in these two disorders, we carried out an exploratory microarray gene expression analysis in lymphoblasts from 8 CH and 10 BD I patients selected for positive response to lithium and 10 healthy controls (CO). Gene expression levels of BD and CH were compared with CO to create two lists of differentially expressed genes. We then matched the two lists and focus on genes showing statistically significant difference and same change direction in both disorders. RNA binding motif protein 3 (RBM3) was the most significantly altered gene in the list (3.17 × 10−13 in BD, 9.44 × 10−14 in CH). Pathway analysis identified protein processing in endoplasmic reticulum as the most significantly enriched. For validation with quantitative reverse transcription PCR (qRT-PCR) using the same samples, we selected seven genes. Among these, we were able to validate the RBM3, nuclear receptor subfamily 1, group D, member 1 (NR1D1), and tryptophan hydroxylase 1 (TPH1). These genes encode for elements involved in circadian rhythm regulation (RBM3 and NR1D1) and in serotonin synthesis (TPH1), processes previously involved in both disorders, and in the mechanism of action of lithium.

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Acknowledgments

This work was supported by Italian Ministry for University, Scientific Research and Technology (PRIN n.2006058195 and n.2008BACT54_002), the Italian Ministry of Health (RFPS-2007-5-640174 and RF-2011-02350537). and Fondazione Gaetano & Mafalda Luce (Milan, Italy). AS is a post-doctoral fellow funded by a grant from the Sardinia Regional Government (P.O.R. Sardegna F.S.E. Operational Program of the Autonomous Region of Sardinia, European Social Fund 2007–2013—Axis IV Human Resources, Objective l.3, Line of Activity l.3.1.). The authors thank the patients involved in the study for the generous collaboration and Davide Catani for his collaboration to prepare figures.

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    Authors and Affiliations

    1. Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Sp 8 Sestu-Monserrato, Km 0.700, 09042, Monserrato, Cagliari, Italy

      Marta Costa, Alessio Squassina, Claudia Pisanu, Donatella Congiu, Paola Niola, Giovanni Severino, Arianna Deidda & Maria Del Zompo

    2. Unit of Child and Adolescent Neuropsychiatry, Laboratory of Molecular Psychiatry and Neurogenetics, University “Campus Bio-Medico”, Rome, Italy

      Ignazio Stefano Piras & Antonio M. Persico

    3. Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy

      Ignazio Stefano Piras & Antonio M. Persico

    4. Center for Advanced Studies, Research, and Development in Sardinia (CRS4), AGCT Program, “Parco Scientifico e Tecnologico della Sardegna”, Pula, Italy

      Andrea Angius

    5. Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy

      Andrea Angius

    6. Unit of Clinical Pharmacology of the University Hospital of Cagliari, Cagliari, Italy

      Caterina Chillotti, Raffaella Ardau, Erminia Stochino, Arianna Deidda & Maria Del Zompo

    7. Department of Psychiatry, Dalhousie University, Halifax, NS, Canada

      Alessio Squassina & Martin Alda

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    1. Marta Costa
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    2. Alessio Squassina
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    Correspondence to Alessio Squassina.

    Additional information

    Marta Costa and Alessio Squassina contributed equally to this work.

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    Table S1

    Differentially expressed genes between BD and CO, with corrected p value < 0.05 and Fold Change (FC) > = 1.3 and FC < =0.77 (XLSX 112 kb)

    Table S2

    Differentially expressed genes between CH and CO, with corrected p value < 0.05 and Fold Change (FC) > = 1.3 and FC < =0.77 (XLSX 261 kb)

    Table S3

    Common genes altered both in BD vs CO and in CH vs CO, considering only genes with corrected P value < 0.05 and Fold Change (FC) > = 1.3 and FC < =0.77 (XLSX 102 kb)

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    Costa, M., Squassina, A., Piras, I.S. et al. Preliminary Transcriptome Analysis in Lymphoblasts from Cluster Headache and Bipolar Disorder Patients Implicates Dysregulation of Circadian and Serotonergic Genes. J Mol Neurosci 56, 688–695 (2015). https://doi.org/10.1007/s12031-015-0567-9

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