Microscopic Particles in Two Fractions of Fresh Cerebrospinal Fluid in Twins with Schizophrenia or Bipolar Disorder and in Healthy Controls

Background

Using scanning electron microscopy, microscopic structures have been identified in fresh cerebrospinal fluid (CSF) in patients with schizophrenia and bipolar disorder, but only rarely in control subjects. However, it has not been determined whether these microscopic particles represent state or trait markers, i.e. if their presence is related to clinical manifestations of the disease or if they also can be found in as yet asymptomatic individuals with a genetic liability. This question can be addressed by studying twins discordant or concordant for schizophrenia or bipolar disorder.

Methodology/Principal Findings

We investigated microscopic structures in CSF in 102 individuals: 21 monozygotic and 16 dizygotic twins affected or not affected with schizophrenia, schizoaffective disorder or bipolar disorder and in 65 healthy singleton controls. A first and a second fraction of CSF was freshly applied on filters and examined by scanning electron microscopy technique. Spherical particles with lipid appearance averaging between 0.1 to 8.0 µm in diameter were detected in the center of the filter as well as located in the margins of larger aggregates binding in a viscous state. Structures were found in 12 of 17 probands, 5 of 12 healthy co-twins and 3 of 73 healthy controls. Thus, a positive microscopic finding significantly increased the likelihood of belonging to the proband group (OR = 48, 95% CL: 8.2–550, p<0.0001) and the co-twin-group (OR = 16, 95% CL: 2.0–218, p = 0.006). Age, sex, history of alcohol abuse or anxiety syndrome, somatic disorder and markers of acute inflammatory activity did not account for group differences; nor did exposure to psychotropic medication.

Conclusion

Presence of microscopic particles in CSF may possibly reflect trait dependent genetic or environmental vulnerability in patients with schizophrenia, schizoaffective disorder or bipolar disorder.     

CRY2 Is Associated with Rapid Cycling in Bipolar Disorder Patients

Background

Bipolar disorder patients often display abnormalities in circadian rhythm, and they are sensitive to irregular diurnal rhythms. CRY2 participates in the core clock that generates circadian rhythms. CRY2 mRNA expression in blood mononuclear cells was recently shown to display a marked diurnal variation and to respond to total sleep deprivation in healthy human volunteers. It was also shown that bipolar patients in a depressive state had lower CRY2 mRNA levels, nonresponsive to total sleep deprivation, compared to healthy controls, and that CRY2 gene variation was associated with winter depression in both Swedish and Finnish cohorts.

Principal Findings

Four CRY2 SNPs spanning from intron 2 to downstream 3′UTR were analyzed for association to bipolar disorder type 1 (n = 497), bipolar disorder type 2 (n = 60) and bipolar disorder with the feature rapid cycling (n = 155) versus blood donors (n = 1044) in Sweden. Also, the rapid cycling cases were compared with bipolar disorder cases without rapid cycling (n = 422). The haplotype GGAC was underrepresented among rapid cycling cases versus controls and versus bipolar disorder cases without rapid cycling (OR = 0.7, P = 0.006−0.02), whereas overrepresentation among rapid cycling cases was seen for AAAC (OR = 1.3−1.4, P = 0.03−0.04) and AGGA (OR = 1.5, P = 0.05). The risk and protective CRY2 haplotypes and their effect sizes were similar to those recently suggested to be associated with winter depression in Swedes.

Conclusions

We propose that the circadian gene CRY2 is associated with rapid cycling in bipolar disorder. This is the first time a clock gene is implicated in rapid cycling, and one of few findings showing a molecular discrimination between rapid cycling and other forms of bipolar disorder.     

Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia,Bipolar Disorder,and Major Depressive Disorder

Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk.     

Contextual Social Cognition Impairments in Schizophrenia and Bipolar Disorder

Background

The ability to integrate contextual information with social cues to generate social meaning is a key aspect of social cognition. It is widely accepted that patients with schizophrenia and bipolar disorders have deficits in social cognition; however, previous studies on these disorders did not use tasks that replicate everyday situations.

Methodology/Principal Findings

This study evaluates the performance of patients with schizophrenia and bipolar disorders on social cognition tasks (emotional processing, empathy, and social norms knowledge) that incorporate different levels of contextual dependence and involvement of real-life scenarios. Furthermore, we explored the association between social cognition measures, clinical symptoms and executive functions. Using a logistic regression analysis, we explored whether the involvement of more basic skills in emotional processing predicted performance on empathy tasks. The results showed that both patient groups exhibited deficits in social cognition tasks with greater context sensitivity and involvement of real-life scenarios. These deficits were more severe in schizophrenic than in bipolar patients. Patients did not differ from controls in tasks involving explicit knowledge. Moreover, schizophrenic patients’ depression levels were negatively correlated with performance on empathy tasks.

Conclusions/Significance

Overall performance on emotion recognition predicted performance on intentionality attribution during the more ambiguous situations of the empathy task. These results suggest that social cognition deficits could be related to a general impairment in the capacity to implicitly integrate contextual cues. Important implications for the assessment and treatment of individuals with schizophrenia and bipolar disorders, as well as for neurocognitive models of these pathologies are discussed.     

The Association between Intelligence Scores and Family History of Psychiatric Disorder in Schizophrenia Patients,Their Siblings and Healthy Controls

Background

The degree of intellectual impairment in schizophrenia patients and their relatives has been suggested to be associated with the degree of familial loading for schizophrenia. Since other psychiatric disorders are also more present in relatives of schizophrenia patients, the definition of family history should be broadened. The association between family history for psychiatric disorder and intelligence scores was investigated in patients with non-affective psychosis, their unaffected siblings and controls.

Methods

A sample of 712 schizophrenia proband families (696 patients and 766 siblings) and 427 healthy control families (517 subjects) participated in this study. Family history of psychiatric disorder was determined while excluding the data of the participating schizophrenia patient. A dichotomous division was made between families with no first- or second degree relative with psychiatric disorder and families with one or more affected relatives. Total intelligence scores were estimated by admission of the short form of the Wechsler Adult Intelligence Scale III.

Results

A significant interaction was found between family history of psychiatric disorder and clinical status (F(2,1086.87)= 4.17; p=.016). Patients with a positive family history of psychiatric disorder obtained higher intelligence scores compared to patients with no family history (mean IQ scores are 95.52 and 92.72) with an opposite effect in controls (mean IQ scores are 108.71 and 111.19). No significant difference was found between siblings of schizophrenia patients with or without a positive family history (mean IQ scores are 102.98 and 103.24).

Conclusion

In patients with schizophrenia, a negative family history of psychiatric disorder was associated with relatively low IQ suggesting that the etiology in these patients may involve environmental or genetic factors which are unique to the patient and are not observed in other relatives. Possible factors include severe environmental stressors containing premature birth or brain injury and genetic factors (e.g de novo Copy Number Variants).     

Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability

Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.     

Facial Emotion Recognition,Misattribution, and Response Time in Schizophrenia and Bipolar Disorder

Neurophysiology - Social cognition abilities are significantly impaired in serious mental illnesses. Facial emotion recognition deficits (FERD) have been consistently reported in schizophrenia...     

Functional Consequences of a Novel Variant of PCSK1

Background

Common single nucleotide polymorphisms (SNPs) in proprotein convertase subtilisin/kexin type 1 with modest effects on PC1/3 in vitro have been associated with obesity in five genome-wide association studies and with diabetes in one genome-wide association study. We here present a novel SNP and compare its biosynthesis, secretion and catalytic activity to wild-type enzyme and to SNPs that have been linked to obesity.

Methodology/Principal Findings

A novel PC1/3 variant introducing an Arg to Gln amino acid substitution at residue 80 (within the secondary cleavage site of the prodomain) (rs1799904) was studied. This novel variant was selected for analysis from the 1000 Genomes sequencing project based on its predicted deleterious effect on enzyme function and its comparatively more frequent allele frequency. The actual existence of the R80Q (rs1799904) variant was verified by Sanger sequencing. The effects of this novel variant on the biosynthesis, secretion, and catalytic activity were determined; the previously-described obesity risk SNPs N221D (rs6232), Q665E/S690T (rs6234/rs6235), and the Q665E and S690T SNPs (analyzed separately) were included for comparative purposes. The novel R80Q (rs1799904) variant described in this study resulted in significantly detrimental effects on both the maturation and in vitro catalytic activity of PC1/3.

Conclusion/Significance

Our findings that this novel R80Q (rs1799904) variant both exhibits adverse effects on PC1/3 activity and is prevalent in the population suggests that further biochemical and genetic analysis to assess its contribution to the risk of metabolic disease within the general population is warranted.     

Cognitive Performance and Cerebrospinal Fluid Biomarkers of Neurodegeneration: A Study of Patients with Bipolar Disorder and Healthy Controls

The purpose of the present study was to investigate if cerebrospinal fluid (CSF) biomarkers of neurodegeneration are associated with cognition in bipolar disorder and healthy controls, respectively. CSF concentrations of total and phosphorylated tau, amyloid beta (Aβ)1-42, ratios of Aβ42/40 and Aβ42/38, soluble amyloid precursor protein α and β, and neurofilament light chain protein were analyzed in relation to neuropsychological performance in 82 euthymic bipolar disorder patients and 71 healthy controls. Linear regression models were applied to account for performance in five cognitive domains using the CSF biomarkers. In patients, the CSF biomarkers explained a significant proportion of the variance (15–36%, p=.002 - <.0005) in all cognitive domains independently of age, medication, disease status, and bipolar subtype I or II. However, the CSF biomarkers specifically mirroring Alzheimer-type brain changes, i.e., P-tau and Aβ1-42, did not contribute significantly. In healthy controls, CSF biomarkers did not explain the variance in cognitive performance. Selected CSF biomarkers of neurodegenerative processes accounted for cognitive performance in persons with bipolar disorder, but not for healthy controls. Specifically, the ratios of Aβ42/40 and Aβ42/38 were consistently associated with altered cognitive performance.     

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

Background

Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders.

Methods

Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium.

Results

The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope.

Conclusions

Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders.     

Relative Risk of Acute Myocardial Infarction in People with Schizophrenia and Bipolar Disorder: A Population-Based Cohort Study

Objective

Despite high mortality associated with serious mental illness, risk of acute myocardial infarction (AMI) remains unclear, especially for patients with bipolar disorder. The main objective was to investigate the relative risk of AMI associated with schizophrenia and bipolar disorders in a national sample.

Method

Using nationwide administrative data, an 11-year historic cohort study was assembled, comprised of cases aged 18 and above who had received a diagnosis of schizophrenia or bipolar disorder, compared to a random sample of all other adults excluding those with diagnoses of serious mental illness. Incident AMI as a primary diagnosis was ascertained. Hazard ratios stratified by age and gender were calculated and Cox regression models were used to adjust for other covariates.

Results

A total of 70,225 people with schizophrenia or bipolar disorder and 207,592 people without serious mental illness were compared. Hazard ratios in men adjusted for age, income and urbanization were 1.15 (95% CI 1.01~1.32) for schizophrenia and 1.37 (1.08~1.73)for bipolar disorder, and in women, 1.85 (1.58~2.18) and 1.88(1.47~2.41) respectively. Further adjustment for treated hypertension, diabetes and hyperlipidaemia attenuated the hazard ratio for men with schizophrenia but not the other comparison groups. Hazard ratios were significantly stronger in women than men and were stronger in younger compared to older age groups for both disorders; however, gender modification was only significant in people with schizophrenia, and age modification only significant in people with bipolar disorder.

Conclusions

In this large national sample, schizophrenia and bipolar disorder were associated with raised risk of AMI in women and in the younger age groups although showed differences in potential confounding and modifying factors.     

pix-1 Controls Early Elongation in Parallel with mel-11 and let-502 in Caenorhabditis elegans

Cell shape changes are crucial for metazoan development. During Caenorhabditis elegans embryogenesis, epidermal cell shape changes transform ovoid embryos into vermiform larvae. This process is divided into two phases: early and late elongation. Early elongation involves the contraction of filamentous actin bundles by phosphorylated non-muscle myosin in a subset of epidermal (hypodermal) cells. The genes controlling early elongation are associated with two parallel pathways. The first one involves the rho-1/RHOA-specific effector let-502/Rho-kinase and mel-11/myosin phosphatase regulatory subunit. The second pathway involves the CDC42/RAC-specific effector pak-1. Late elongation is driven by mechanotransduction in ventral and dorsal hypodermal cells in response to body-wall muscle contractions, and involves the CDC42/RAC-specific Guanine-nucleotide Exchange Factor (GEF) pix-1, the GTPase ced-10/RAC and pak-1.In this study, pix-1 is shown to control early elongation in parallel with let-502/mel-11, as previously shown for pak-1. We show that pix-1, pak-1 and let-502 control the rate of elongation, and the antero-posterior morphology of the embryos. In particular, pix-1 and pak-1 are shown to control head, but not tail width, while let-502 controls both head and tail width. This suggests that let-502 function is required throughout the antero-posterior axis of the embryo during early elongation, while pix-1/pak-1 function may be mostly required in the anterior part of the embryo. Supporting this hypothesis we show that low pix-1 expression level in the dorsal-posterior hypodermal cells is required to ensure high elongation rate during early elongation.     

KIR,HLA, and IL28B Variant Predict Response to Antiviral Therapy in Genotype 1 Chronic Hepatitis C Patients in Japan

Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR) in combination with its cognate human leukocyte antigen (HLA) ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL) 28B (rs8099917) in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-α2b (PEG-IFN) and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR) to treatment (P = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16) as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1-HLA-Bw4 in responders (P = 0.0019), whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067). In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV.     

Rare Risk Variants Identification by Identity-by-Descent Mapping and Whole-Exome Sequencing Implicates Neuronal Development Pathways in Schizophrenia and Bipolar Disorder

Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable disorders with an estimated co-heritability of 68%. Hundreds of common alleles have been implicated, but recently a role for rare, high-penetrant variants has been also suggested in both disorders. This study investigated a familial cohort of SCZ and BPD patients from a closed population sample, where the high recurrence of the disorders and the homogenous genetic background indicate a possible enrichment in rare risk alleles. A total of 230 subjects (161 cases, 22 unaffected relatives, and 47 controls) were genetically investigated through an innovative strategy that integrates identity-by-descent (IBD) mapping and whole-exome sequencing (WES). IBD analysis allowed to track high-risk haplotypes (IBD_risk) shared exclusively by multiple patients from different families and possibly carrying the most penetrant alleles. A total of 444 non-synonymous sequence variants, of which 137 disruptive, were identified in IBD_risk haplotypes by WES. Interestingly, gene sets previously implicated in SCZ (i.e., post-synaptic density (PSD) proteins, voltage-gated calcium channels (VGCCs), and fragile X mental retardation protein (FMRP) targets) were found significantly enriched in genes carrying IBD_risk variants. Further, IBD_risk variants were preferentially affecting genes involved in the extracellular matrix (ECM) biology and axon guidance processes which appeared to be functionally connected in the pathway-derived meta-network analysis. Results thus confirm rare risk variants as key factors in SCZ and BPD pathogenesis and highlight a role for the development of neuronal connectivity in the etiology of both disorders.     

Description of third instar larvae of Ceratitis fasciventris,C. anonae,C. rosa (FAR complex) and C. capitata (Diptera,Tephritidae)

Third instar larvae of members of the Ceratitis FAR complex, including Ceratitisfasciventris (Bezzi), Ceratitisanonae Graham, and Ceratitisrosa Karsch are described and compared with those of Ceratitiscapitata (Wiedemann). Diagnostic characters, such as presence vs. absence of a secondary tooth on the mandibles, previously used to separate Ceratitiscapitata from Ceratitisrosa, are shown to vary in each species. Significant variation in diagnostic morphological characters among populations of Ceratitisrosa from east and south Africa is documented; however, the differences are not simply congruent with the R1 and R2 designations based on other studies. Quantitative measures of numerous morphological characters are consistently smaller in the larvae of Ceratitisfasciventris and distinguish them from other species of the FAR complex. Larvae of Ceratitiscapitata can be distinguished from those of the FAR complex by characters such as absence of accessory plates of the oral ridges, the shape of the anterior spiracle, and the pattern of dorsal spinules. Previous studies indicated that absence of accessory lobes separate the genus Ceratitis from Bactrocera, but this is shown to be incorrect, as accessory lobes are in fact present in several species of Ceratitis.     

Association between ST8SIA2 and the Risk of Schizophrenia and Bipolar I Disorder across Diagnostic Boundaries

Background

Findings from family studies and recent genome-wide association studies have indicated overlap in the risk genes between schizophrenia and bipolar disorder (BD). After finding a linkage between the ST8SIA2 (ST8 alpha-N-acetyl-neuraminide alpha-2, 8-sicalyltransferase 2 gene) locus (15q26) and mixed families with schizophrenia and BD, several studies have reported a significant association between this gene and schizophrenia or BD. We investigated the genetic association between ST8SIA2 and both schizophrenia and BD in the Korean population.

Methods

A total of 582 patients with schizophrenia, 339 patients with BD, and 502 healthy controls were included. Thirty-one tag single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and three other SNPs showing significant associations in previous studies were genotyped. The associations were evaluated by logistic regression analysis using additive, dominant, and recessive genetic models.

Results

Fourteen of 34 SNPs showed a nominally significant association (p < 0.05) with at least one diagnostic group. These association trends were strongest for the schizophrenia and combined schizophrenia and bipolar I disorder (BD-I) groups. The strongest association was observed in rs11637898 for schizophrenia (p = 0.0033) and BD-I (p = 0.0050) under the dominant model. The association between rs11637898 and the combined schizophrenia and BD-I group (p = 0.0006, under the dominant model) remained significant after correcting for multiple testing.

Discussion

We identified a possible role of ST8SIA2 in the common susceptibility of schizophrenia and BD-I. However, no association trend was observed for bipolar II disorder. Further efforts are needed to identify a specific phenotype associated with this gene crossing the current diagnostic categories.