RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder
Open accessAbstract
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.
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Previous studies identified alterations in local splicing events in ASD and in smaller cohorts in SCZ and BD.
“Previous studies have identified alterations in local splicing events in ASD (19, 30) and in smaller cohorts in SCZ (2, 24) and BD (31).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [31]
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- Authors
- Akula, N., Barb, J., Jiang, X., Wendland, J. R., Choi, K. H., Sen, S. K., Hou, L., Chen, D. T. W., Laje, G., Johnson, K., Lipska, B. K., Kleinman, J. E., Corrada-Bravo, H., Detera-Wadleigh, S., Munson, P. J., & McMahon, F. J.
- Affiliations
- National Institutes of Health (US)
- Uniformed Services University of the Health Sciences (US)
- United States Department of Health and Human Services (US)
- Lieber Institute for Brain Development (US)
- Corresponding author
- Akula, N
- Venue
- Molecular Psychiatry
- Published
- 2014-01-07
- Volume
- 19
- Issue
- 11
- Pages
- 1179-1185
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5560442
- OpenAlex
- W1977521681
- Cited by
- 116
- References
- 56
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 8 · 2023: 3 · 2022: 7 · 2021: 13 · 2020: 10 · 2019: 13 · 2018: 10 · 2017: 10 · 2016: 13 · 2015: 15 · 2014: 5
- FWCI
- 10.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Stanley Medical Research Institute
- National Institutes of Health (ZIACT000277)
- U.S. Public Health Service (ZIAMH002810)
- National Institute of Mental Health (K99MH085098, ZIAMH002810)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- bipolar disorder, brain transcriptome, dorsolateral prefrontal cortex, differentially expressed genes, long non-coding RNA, neuroplasticity, circadian rhythm, ABCG2, SRSF5, gene expression dysregulation
- MeSH terms
- Adult, Aged, Bipolar Disorder, Circadian Rhythm, Female, Humans, Male, Middle Aged, Neuronal Plasticity, Meta-Analysis as Topic, Polymerase Chain Reaction, Prefrontal Cortex, Sequence Analysis, RNA, GTP Phosphohydrolases, Principal Component Analysis, Microarray Analysis, Genome-Wide Association Study, Young Adult, Transcriptome
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