Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics, and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads, and prioritize genes for functional follow-up studies.

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Any repeatedly performed action is characterized by endogenous variability, affecting both speed and accuracy—for a large part presumably caused by fluctuations in underlying brain and body states. The current research questions concerned (a) whether such states are accessible to us and (b) whether we can act upon this information to reduce variability. For example, when playing a game of darts, there is an implicit assumption that people can wait to throw until they are in the right perceptual-attentional state. If this is true, taking away the ability to self-pace the game should worsen performance. We first tested precisely this assumption asking participants to play darts in a self-paced and a fixed-paced condition. There was no benefit of self-pacing, showing that participants were unable to use such control to improve their performance and reduce their variability. Next, we replicated these findings in 2 computer-based tasks, in which participants performed a rapid action-selection and a visual detection task in 1 self-paced and 3 forced-paced conditions. Over 4 different empirical tests, we show that the self-paced condition did not lead to improved performance or reduced variability, nor to reduced temporal dependencies in the reaction time (RT) series. Overall, it seems that, if people have any access to their fluctuating performance-relevant inner states, this access is limited and not relevant for upcoming performance.

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