While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution ...of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 1.4,16.0, p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 1.7,22.6, p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 1.5,16.8, p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.
► Strong association of rare de novo CNVs with bipolar disorder ► Rare de novo CNVs influence age at disease onset in bipolar disorder ► Replication of earlier findings of a high frequency of de novo CNVs in schizophrenia
Objectives
Cognitive dysfunction affects a significant proportion of people with bipolar disorder (BD), but the cause, trajectory and correlates of such dysfunction remains unclear. Increased ...understanding of these factors is required to progress treatment development for this symptom dimension.
Methods
This paper provides a critical overview of the literature concerning the trajectories and emerging correlates of cognitive functioning in BD. It is a narrative review in which we provide a qualitative synthesis of current evidence concerning clinical, molecular, neural and lifestyle correlates of cognitive impairment in BD across the lifespan (in premorbid, prodromal, early onset, post‐onset, elderly cohorts).
Results
There is emerging evidence of empirical links between cognitive impairment and an increased inflammatory state, brain structural abnormalities and reduced neuroprotection in BD. However, evidence regarding the progressive nature of cognitive impairment is mixed, since consensus between different cross‐sectional data is lacking and does not align to the outcomes of the limited longitudinal studies available. Increased recognition of cognitive heterogeneity in BD may help to explain some inconsistencies in the extant literature.
Conclusions
Large, longitudinally focussed studies of cognition and its covariation alongside biological and lifestyle factors are required to better define cognitive trajectories in BD, and eventually pave the way for the application of a precision medicine approach for individual patients in clinical practice.
Bipolar disorder is a chronically disabling psychiatric disorder characterized by manic states that is often interspersed with periods of depression whose neurobiology remains largely unknown. There ...is, however, increasing evidence that white matter (WM) abnormalities may play an important role in the neurobiology of the disorder. In this review we critically evaluate evidence for WM abnormalities in bipolar disorder obtained from neuroimaging, neuropathological, and genetic research. Increased rates of white matter hyperintensities, regional volumetric abnormalities, abnormal water diffusion along prefrontal-subcortical tracts, fewer oligodendrocytes in prefrontal WM, and alterations in the expression of myelin- and oligodendrocyte-related genes are among the most consistent findings. Abnormalities converge in the prefrontal WM and, in particular, tracts that connect prefrontal regions and subcortical gray matter structures known to be involved in emotion. Taken together, the evidence supports and clarifies a model of BD that involves disconnectivity in regions implicated in emotion generation and regulation.
Bipolar disorder (BD) is a complex illness with variability at the level of symptom presentation, clinical course, cognitive capacity, and everyday function. Cognition is a key predictor of ...functional disability in BD, however, much remains unknown about the development and presentation of cognitive dysfunction in BD. Studies have shown that 30-50% of affectively stable people with BD are indistinguishable from healthy individuals in terms of cognitive presentation. In contrast, many people with BD have moderate to severe cognitive deficits, in some cases on par with what is typically observed in schizophrenia (SZ). Recent research efforts have aimed to parse this cognitive heterogeneity using unsupervised statistical techniques, resulting in more homogeneous subgroups. This method has provided new insights into the clinical and biological predictors of a potentially – neuroprogressive – declinin – gcognitive course in BD. Future studies that include detailed longitudinal follow-up in large BD cohorts hold promise for guiding the development of novel treatments that reach beyond the primary affective symptoms and target functionally relevant outcomes to promote full recovery.
Cognitive impairment is emerging as an important therapeutic target in patients with psychiatric illnesses, including major depressive disorder (MDD). The objective of this general overview is to ...briefly review the evidence for cognitive impairment in MDD and to summarize a representative sample of cognitive assessment tools currently available to assess cognitive function in depressed patients. Study results in MDD patients with cognitive dysfunction are somewhat inconsistent, likely due to the heterogeneity of the disorder as well as the use of diverse assessment tools. Measuring cognitive changes in this population is challenging. Cognitive symptoms are typically less severe than in patients with schizophrenia and bipolar disorder, requiring greater sensitivity than afforded by existing tools. Preliminary evidence suggests antidepressant treatments may improve cognitive functioning as a direct result of ameliorating depressive symptoms; however, any procognitive effects have not been elucidated. To evaluate antidepressant efficacy in MDD patients with cognitive dysfunction, a standardized cognitive battery for use in clinical trials is essential.
Schizophrenia and bipolar disorder share aspects of phenomenology and neurobiology and thus may represent a continuum of disease. Few studies have compared connectivity across the brain in these ...disorders or investigated their functional correlates.
We used resting-state functional magnetic resonance imaging to evaluate global and regional connectivity in 32 healthy controls, 19 patients with bipolar disorder, and 18 schizophrenia patients. Patients also received comprehensive neuropsychological and clinical assessments. We computed correlation matrices among 266 regions of interest within the brain, with the primary dependent measure being overall global connectivity strength of each region with every other region.
Patients with schizophrenia had significantly lower global connectivity compared with healthy controls, whereas patients with bipolar disorder had global connectivity intermediate to and significantly different from those of patients with schizophrenia and healthy controls. Post hoc analyses revealed that compared with healthy controls, both patient groups had significantly lower connectivity in the paracingulate gyrus and right thalamus. Patients with schizophrenia also had significantly lower connectivity in the temporal occipital fusiform cortex, left caudate nucleus, and left thalamus compared with healthy controls. There were no significant differences among the patient groups in any of these regions. Lower global connectivity among all patients was associated with worse neuropsychological and clinical functioning, but these effects were not specific to any patient group.
These findings are consistent with the hypothesis that schizophrenia and bipolar disorder may represent a continuum of global disconnectivity in the brain but that regional functional specificity may not be evident.
Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates ...different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.
► FEZ1 regulates dendritic growth and soma size during adult hippocampal neurogenesis ► FEZ1 interacts with DISC1 in regulating dendritic growth of newborn neurons ► FEZ1 and NDEL1 differentially mediate DISC1-dependent neuronal development ► Epistasis between FEZ1 and DISC1 influences the risk for schizophrenia
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