title: RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder.
abstract: RNA-sequencing (RNA-seq) is a powerful technique to investigate the complexity of gene expression in the human brain. We used RNA-seq to survey the brain transcriptome in high-quality postmortem dorsolateral prefrontal cortex from 11 individuals diagnosed with bipolar disorder (BD) and from 11 age- and gender-matched controls. Deep sequencing was performed, with over 350 million reads per specimen. At a false discovery rate of <5%, we detected five differentially expressed (DE) genes and 12 DE transcripts, most of which have not been previously implicated in BD. Among these, Prominin 1/CD133 and ATP-binding cassette-sub-family G-member2 (ABCG2) have important roles in neuroplasticity. We also show for the first time differential expression of long noncoding RNAs (lncRNAs) in BD. DE transcripts include those of serine/arginine-rich splicing factor 5 (SRSF5) and regulatory factor X4 (RFX4), which along with lncRNAs have a role in mammalian circadian rhythms. The DE genes were significantly enriched for several Gene Ontology categories. Of these, genes involved with GTPase binding were also enriched for BD-associated SNPs from previous genome-wide association studies, suggesting that differential expression of these genes is not simply a consequence of BD or its treatment. Many of these findings were replicated by microarray in an independent sample of 60 cases and controls. These results highlight common pathways for inherited and non-inherited influences on disease risk that may constitute good targets for novel therapies.
authors.affiliation: Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: N
authors.initials: N
authors.lastname: Akula
authors.affiliation: Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Barb
authors.affiliation: Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Wendland
authors.affiliation: Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Choi
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: S K
authors.identifier: 000000025781721X
authors.initials: SK
authors.lastname: Sen
authors.affiliation: Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Hou
authors.affiliation: Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: D T W
authors.initials: DT
authors.lastname: Chen
authors.affiliation: Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Laje
authors.affiliation: Bioinformatics Section, Information Technology & Bioinformatics Program, Division of Intramural Research, National Institute of Neurological Disorders & Stroke, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Human Brain Collection Core, Division of Intramural Research Programs, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Lipska
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Kleinman
authors.affiliation: Department of Computer Science, Institute for Advanced Computer Studies and Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Corrada-Bravo
authors.affiliation: Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Detera-Wadleigh
authors.affiliation: Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Munson
authors.affiliation: Human Genetics Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: F J
authors.initials: FJ
authors.lastname: McMahon
mesh_terms: D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D046228:Microarray Analysis; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D017397:Prefrontal Cortex / Q000378:metabolism*; D025341:Principal Component Analysis; D017423:Sequence Analysis, RNA / Q000379:methods; D059467:Transcriptome; D055815:Young Adult
chemical_list: D020558:GTP Phosphohydrolases