The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders
2018
Major
mood disorders, which primarily include bipolar disorder and
majordepressive disorder, are the leading cause of disability worldwide and pose a
majorchallenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed
protocadherin17 (PCDH17) as a susceptibility gene for
major
mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with
major
mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of
dendritic spinesin the brains of patients with
major
mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for
major
mood disordersinvolved in synaptic function and related intermediate phenotypes.
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