title: Novel integrative genomic tool for interrogating lithium response in bipolar disorder.
abstract: We developed a novel integrative genomic tool called GRANITE (Genetic Regulatory Analysis of Networks Investigational Tool Environment) that can effectively analyze large complex data sets to generate interactive networks. GRANITE is an open-source tool and invaluable resource for a variety of genomic fields. Although our analysis is confined to static expression data, GRANITE has the capability of evaluating time-course data and generating interactive networks that may shed light on acute versus chronic treatment, as well as evaluating dose response and providing insight into mechanisms that underlie therapeutic versus sub-therapeutic doses or toxic doses. As a proof-of-concept study, we investigated lithium (Li) response in bipolar disorder (BD). BD is a severe mood disorder marked by cycles of mania and depression. Li is one of the most commonly prescribed and decidedly effective treatments for many patients (responders), although its mode of action is not yet fully understood, nor is it effective in every patient (non-responders). In an in vitro study, we compared vehicle versus chronic Li treatment in patient-derived lymphoblastoid cells (LCLs) (derived from either responders or non-responders) using both microRNA (miRNA) and messenger RNA gene expression profiling. We present both Li responder and non-responder network visualizations created by our GRANITE analysis in BD. We identified by network visualization that the Let-7 family is consistently downregulated by Li in both groups where this miRNA family has been implicated in neurodegeneration, cell survival and synaptic development. We discuss the potential of this analysis for investigating treatment response and even providing clinicians with a tool for predicting treatment response in their patients, as well as for providing the industry with a tool for identifying network nodes as targets for novel drug discovery.
authors: Molecular Neurobiology Section, National Institute of Mental Health (NIMH), National Institutes of Health, Bethesda, MD, USA.
authors: J G
authors: JG
authors: Hunsberger
authors: Molecular Neurobiology Section, National Institute of Mental Health (NIMH), National Institutes of Health, Bethesda, MD, USA.
authors: F L
authors: FL
authors: Chibane
authors: National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD, USA.
authors: A G
authors: AG
authors: Elkahloun
authors: Bioinformatics and Computational Biosciences Branch (BCBB), Office of Cyber Infrastructure and Computational Biology (OCICB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
authors: R
authors: R
authors: Henderson
authors: Lockheed Martin Corporation, IS&GS, Bethesda, MD, USA.
authors: R
authors: R
authors: Singh
authors: KG Science Associates, LLC, San Diego, CA, USA.
authors: J
authors: J
authors: Lawson
authors: 1] McGill Group for Suicide Studies, Douglas Mental Health Institute, McGill University, Montreal, Quebec, Canada [2] Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors: C
authors: C
authors: Cruceanu
authors: Bioinformatics and Computational Biosciences Branch (BCBB), Office of Cyber Infrastructure and Computational Biology (OCICB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, USA.
authors: V
authors: V
authors: Nagarajan
authors: McGill Group for Suicide Studies, Douglas Mental Health Institute, McGill University, Montreal, Quebec, Canada.
authors: G
authors: G
authors: Turecki
authors: Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors: A
authors: A
authors: Squassina
authors: McGill Group for Suicide Studies, Douglas Mental Health Institute, McGill University, Montreal, Quebec, Canada.
authors: C D
authors: CD
authors: Medeiros
authors: Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors: M
authors: M
authors: Del Zompo
authors: Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors: G A
authors: GA
authors: Rouleau
authors: Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: M
authors: M
authors: Alda
authors: Molecular Neurobiology Section, National Institute of Mental Health (NIMH), National Institutes of Health, Bethesda, MD, USA.
authors: D-M
authors: DM
authors: Chuang
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy*; D005260:Female; D023281:Genomics / Q000295:instrumentation / Q000379:methods; D006801:Humans; D018020:Lithium Compounds / Q000627:therapeutic use*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010597:Pharmacogenetics / Q000295:instrumentation / Q000379:methods*; D013223:Statistics as Topic / Q000295:instrumentation / Q000379:methods*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D018020:Lithium Compounds; D035683:MicroRNAs
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