Molecular neurobiological clues to the pathogenesis of bipolar disorder

•Bipolar disorder has a large genetic component, with many loci involved.•Leading genes include CACNA1C and ANK3.•There is genetic convergence on calcium signalling and other pathways.•Genetic mouse models, and stem cells, are shedding light on pathogenesis.•The advances have potential therapeutic benefits, but these remain distant.

Bipolar disorder is a serious psychiatric disorder, with a high heritability and unknown pathogenesis. Recent genome-wide association studies have identified the first loci, implicating genes such as CACNA1C and ANK3. The genes highlight several pathways, notably calcium signalling, as being of importance. Molecular studies suggest that the risk variants impact on gene regulation and expression. Preliminary studies using reprogrammed patient-derived cells report alterations in the transcriptome and in cellular adhesion and differentiation. Mouse models show that genes involved in circadian biology, acting via dopaminergic effects, reproduce aspects of the bipolar phenotype. These findings together represent significant advances in identification of the genetic and molecular basis of bipolar disorder, yet we are still far from an integrated, evidence-based understanding of its aetiopathogenesis.