RNA sequencing unlocks bipolar secrets

from medwireNews By Eleanor McDermid

Mol Psychiatry 2014; Advance online publication

An RNA sequencing study of patients with bipolar disorder has shown altered expression of genes and transcripts, including those involved in neuroplasticity and circadian rhythms.

Nirmala Akula (National Institute of Mental Health, Bethesda, Maryland, USA) and colleagues measured expression levels of 25,017 genes and 182,884 individual transcripts in postmortem dorsolateral prefrontal cortex tissue from 11 patients with bipolar disorder and 11 mentally healthy controls matched for age and gender.

Five genes had significantly altered expression in the patients versus controls at a false-discovery rate of less than 5%, with four being downregulated and one – a long noncoding RNA – being upregulated.

In particular, the authors highlight the reduced expression of PROM1/CD133 and ABCG2, which are normally highly expressed in neural stem cells. “This finding is consistent with the idea of reduced neuroplasticity in [bipolar disorder],” they write in Molecular Psychiatry.

rna-seq

They also note the underexpression of FLI1, defects in which result in impaired neural crest development.

At the transcript level, 12 transcripts had altered expression between patients and controls, with eight being downregulated in the patients, including three with a role in sleep or circadian rhythms.

Changes in these genes and transcripts were highly significant, but at a nominal statistical level, 1225 genes and 2776 transcripts were differently expressed between patients and controls. In this wider pool of altered genes and transcripts, patients had a fivefold increase in those that fell into the Gene Ontology category transmembrane receptor protein phosphatase activity.

They also had a twofold increase of genes and transcripts in several other categories, including the GTPase binding category. Genes in this category had an increased representation of single nucleotide polymorphisms found to be associated with bipolar disorder in a recent genome-wide association study, suggesting a functional role for these genes.

“GTPases are often highly ‘druggable’ targets, so may be particularly promising leads for the development of novel therapeutics,” observes the team.

The researchers provide support for their RNA sequencing results with gene expression microarray analysis of a further 22 patients and 26 controls, which revealed significant overlap of genes that had altered expression in bipolar patients using both methods.

Akula et al note that analysis of RNA sequencing data may also provide information about “novel genes, RNA-editing and allele-specific expression,” and conclude: “We have probably uncovered only a fraction of what these data may reveal about [bipolar disorder].”

medwireNews (www.medwirenews.com) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2014

Akula N, Barb J, Jiang X, Wendland JR, Choi KH, Sen SK, Hou L, Chen DT, Laje G, Johnson K, Lipska BK, Kleinman JE, Corrada-Bravo H, Detera-Wadleigh S, Munson PJ, McMahon FJ. (2014) RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder. Mol Psychiatry [Epub ahead of print]. [abstract]

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