Structural asymmetries in the supratemporal plane of the human brain are often cited as the anatomical basis for the lateralization of language predominantly to the left hemisphere. However, similar asymmetries are found for structures mediating earlier events in the auditory processing stream, suggesting that functional lateralization may occur even at the level of primary auditory cortex. We tested this hypothesis using functional magnetic resonance imaging to evaluate human auditory cortex responses to monaurally presented tones. Relative to silence, tones presented separately to either ear produced greater activation in left than right Heschl's gyrus, the location of primary auditory cortex. This functional lateralization for primary auditory cortex is distinct from the contralateral dominance reported for other mammals, including nonhuman primates, and may have contributed to the evolution of a unique role for the left hemisphere in language processing.
RNA splicing is a key mechanism linking genetic variation and complex diseases, including schizophrenia. Splicing profiles are particularly diverse in the brain, but it is difficult to accurately identify and quantify full-length isoforms using standard approaches. CACNA1C is a large gene that shows robust genetic associations with several psychiatric disorders and encodes multiple, functionally-distinct voltage-gated calcium channels via alternative splicing. We combined long-range PCR with nanopore sequencing to characterise the full-length coding sequences of the CACNA1C gene in human brain. We show that its splice isoform profile varies between brain regions and is substantially more complex than currently appreciated: we identified 38 novel exons and 83 high confidence novel isoforms, many of which are predicted to alter protein function. Our findings demonstrate the capability of long-read amplicon sequencing to effectively characterise human splice isoform diversity, while the accurate characterisation of CACNA1C isoforms will facilitate the identification of disease-linked isoforms.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
Bipolar disorder (BD) is a leading cause of global disability. Its biological basis is unknown, and its treatment unsatisfactory. Here, we review two recent areas of progress. First, the discovery of risk genes and their implications, with a focus on voltage-gated calcium channels as part of the disease process and as a drug target. Second, facilitated by new technologies, it is increasingly apparent that the bipolar phenotype is more complex and nuanced than simply one of recurring manic and depressive episodes. One such feature is persistent mood instability, and efforts are underway to understand its mechanisms and its therapeutic potential. BD illustrates how psychiatry is being transformed by contemporary neuroscience, genomics, and digital approaches. Bipolar Disorder and the New Psychiatry Psychiatry still relies largely on 19th-Century diagnostic categories. These are based on clusters of symptoms rather than biological markers, and are treated with drugs discovered serendipitously several decades ago. BD typifies this unsatisfactory state of affairs. Although its name has changed [it was formerly known as manic depression (see Glossary)], its cardinal features, and how it is assessed and treated (Box 1) have barely altered. An important reason for this stagnation has been the lack of any real traction on its causes and underlying biology, beyond its well-established high heritability [1]. Although there is evidence for altered structural and functional brain connectivity [2-4], and changes in markers of oxidative stress [5], mitochondrial function [6], inflammation [7], circadian rhythms [8], and dopamine [9], it remains difficult to integrate these diverse findings, and to disentangle causative changes from those that are secondary to the disorder and its treatment. The situation is belatedly improving. While optimism must be tempered by appreciation of the many complexities, there are realistic prospects for a transformation in our understanding of BD and how it is diagnosed and treated. Here, we highlight two areas of current interest: the discovery of the first BD risk genes and their implications, and the application of novel technologies with the potential to refine, or redefine, the BD phenotype. These developments exemplify how genomics, neuroscience, and digital technologies are heralding a new era for psychiatry. For broader reviews of BD, see [10,11].
Risk-taking behaviour is a key component of several psychiatric disorders and could influence lifestyle choices such as smoking, alcohol use and diet. As a phenotype, risk-taking behaviour therefore fits within a Research Domain Criteria (RDoC) approach, whereby identifying genetic determinants of this trait has the potential to improve our understanding across different psychiatric disorders. Here we report a genome wide association study in 116 255 UK Biobank participants who responded yes/no to the question “Would you consider yourself a risk-taker?” Risk-takers (compared to controls) were more likely to be men, smokers and have a history of psychiatric disorder. Genetic loci associated with risk-taking behaviour were identified on chromosomes 3 (rs13084531) and 6 (rs9379971). The effects of both lead SNPs were comparable between men and women. The chromosome 3 locus highlights CADM2, previously implicated in cognitive and executive functions, but the chromosome 6 locus is challenging to interpret due to the complexity of the HLA region. Risk-taking behaviour shared significant genetic risk with schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and post-traumatic stress disorder, as well as with smoking and total obesity. Despite being based on only a single question, this study furthers our understanding of the biology of risk-taking behaviour, a trait which has a major impact on a range of common physical and mental health disorders.
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