RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder

• Published in: Molecular psychiatry Vol. 19; no. 11; pp. 1179 - 1185
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2014; Nature Publishing Group
• Subjects: 631/337/2019; 631/378/1385; 692/699/476/1333; Adult; Aged; Behavioral Sciences; Bioinformatics; Biological Psychology; Bipolar disorder; Bipolar Disorder - genetics; Bipolar Disorder - metabolism; Brain; Brain research; Circadian rhythm; Circadian Rhythm - genetics; Circadian Rhythm - physiology; Circadian rhythms; DNA microarrays; Female; Gender; Gene expression; Genetic aspects; Genetic research; Genome-wide association studies; Genome-Wide Association Study; Genomes; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Humans; Independent sample; Information technology; Male; Medicine; Medicine & Public Health; Mental health; Meta-Analysis as Topic; Methods; Microarray Analysis; Middle Aged; Neural plasticity; Neuronal Plasticity - genetics; Neuronal Plasticity - physiology; Neurosciences; Non-coding RNA; Ontology; original-article; Pharmacotherapy; Polymerase Chain Reaction; Prefrontal cortex; Prefrontal Cortex - metabolism; Principal Component Analysis; Psychiatry; Ribonucleic acid; RNA; RNA sequencing; Sequence Analysis, RNA - methods; Single-nucleotide polymorphism; Splicing factors; Transcriptome; Transcriptomes; Young Adult; United States > US; long noncoding RNAs; genome-wide association studies; gene expression; Gene Ontology; microarrays
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2013.170

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.