Publications by authors named "Boris Chaumette"

30 Publications

  • Page 1 of 1

Influence of polygenic risk scores for schizophrenia and resilience on the cognition of individuals at-risk for psychosis.

Transl Psychiatry 2021 Oct 9;11(1):518. Epub 2021 Oct 9.

Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM, U1266, Paris, France.

Cognitive impairment is a core feature of schizophrenia which precedes the onset of full psychotic symptoms, even in the ultra-high-risk stage (UHR). Polygenic risk scores (PRS) can be computed for many psychiatric disorders and phenotyping traits, including scores for resilience. We explored the correlations between several PRS and neurocognition in UHR individuals. We included 107 UHR individuals; 29.9% of them converted to psychosis (UHR-C) while 57.0% did not (UHR-NC) during the 1-year follow-up. Cognitive performances were assessed with the Wechsler Adult Intelligence Scale estimating the Intelligence Quotient (IQ), the Trail Making Test, the verbal fluency, the Stroop test, and the Wisconsin card sorting test. Linear regression models were used to test their association with the PRS for schizophrenia, bipolar disorder, major depression, ADHD, cross-disorders, cognitive performance, intelligence, education attainment, and resilience to schizophrenia. UHR-C had a lower IQ than UHR-NC. The PRS for schizophrenia negatively correlated with IQ, while the PRS for cognitive performance and for resilience positively correlated with IQ. PRS for schizophrenia showed a significant correlation with working memory and processing speed indices. PRS for schizophrenia showed a higher effect on IQ in UHR-NC, and UHR-NC with high PRS for schizophrenia had a similar IQ as UHR-C. Conversely, UHR-C with a high PRS for resilience performed as well as UHR-NC. Our findings suggest that cognitive deficits may predate the onset of psychosis. The genetic architecture of schizophrenia seems to impacts the cognition in UHR-NC. Cognition is also mediated by PRS for resilience.
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http://dx.doi.org/10.1038/s41398-021-01624-zDOI Listing
October 2021

Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series.

Front Psychiatry 2021 21;12:669446. Epub 2021 Jun 21.

Child and Adolescent Psychiatric Unit, URHEA, CHSR Sotteville les Rouen, Sotteville les Rouen, France.

Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP's polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6. Hence, in case of CYP's polymorphisms in youth, the use of fluvoxamine as add-on to clozapine could help in reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile as it has already been described in adults. We report four pediatric cases with severe psychiatric disorders underlying our experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore the clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drug interactions when fluvoxamine is considered. Hence, we propose a detailed step-by-step multidisciplinary protocol.
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http://dx.doi.org/10.3389/fpsyt.2021.669446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255476PMC
June 2021

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

Int J Mol Sci 2021 Jun 26;22(13). Epub 2021 Jun 26.

Institute of Psychiatry and Neuroscience of Paris (IPNP), Université de Paris, INSERM U1266, F-75014 Paris, France.

Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.
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http://dx.doi.org/10.3390/ijms22136881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269187PMC
June 2021

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

Int J Mol Sci 2021 Jun 26;22(13). Epub 2021 Jun 26.

Institute of Psychiatry and Neuroscience of Paris (IPNP), Université de Paris, INSERM U1266, F-75014 Paris, France.

Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.
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http://dx.doi.org/10.3390/ijms22136881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269187PMC
June 2021

Association between COMT methylation and response to treatment in children with ADHD.

J Psychiatr Res 2021 03 7;135:86-93. Epub 2021 Jan 7.

Douglas Mental Health University Institute, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada. Electronic address:

Background: COMT had been considered a promising candidate gene in pharmacogenetic studies in ADHD; yet the findings from these studies have been inconsistent. Part of these inconsistencies could be related to epigenetic mechanisms (including DNA methylation). Here we investigated the role of genetic variants of the COMT gene on the methylation levels of CpG sites in the same gene and explored the effect of methylation on methylphenidate (MPH) and placebo (PBO) response in children with ADHD.

Methods: Two hundred and thirty children with ADHD (6-12 years) participated in a randomized, double-blind, placebo-controlled crossover trial with MPH. Univariate analysis was performed to examine the associations between genotypes in the COMT gene and DNA methylation in the same genetic loci. Association between the DNA methylation of 11 CpG sites and PBO/MPH responses were then assessed using spearman's correlation analysis in 212 children. Multiple linear regression analyses were performed to test the interaction between these factors while accounting for sex.

Results: Associations were observed between specific genetic variants and methylation level of cg20709110. Homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), Val/Val (rs4680) and the haplotype (ACCVal/GCGVal) were significantly associated with higher level of methylation. This CpG showed a significant correlation with placebo response (r = -0.15, P = 0.045) according to the teachers' evaluation, and a close-to significance correlation with response to MPH according to parents' evaluation (r = -0.134, p = 0.051). Regression analysis showed that in the model including rs4818, sex and DNA methylation of cg20709110 contributed significantly to treatment response.

Conclusions: These preliminary results could provide evidence for the effect of genetic variations on methylation level and the involvement of the epigenetic variation of COMT loci in modulating the response to treatment in ADHD.

Trial Registration: clinicaltrials.gov, number NCT00483106.
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http://dx.doi.org/10.1016/j.jpsychires.2021.01.008DOI Listing
March 2021

Epigenetics in bipolar disorder: a critical review of the literature.

Psychiatr Genet 2021 02;31(1):1-12

Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris.

Introduction: Bipolar disorder (BD) is a chronic, disabling disease characterised by alternate mood episodes, switching through depressive and manic/hypomanic phases. Mood stabilizers, in particular lithium salts, constitute the cornerstone of the treatment in the acute phase as well as for the prevention of recurrences. The pathophysiology of BD and the mechanisms of action of mood stabilizers remain largely unknown but several pieces of evidence point to gene x environment interactions. Epigenetics, defined as the regulation of gene expression without genetic changes, could be the molecular substrate of these interactions. In this literature review, we summarize the main epigenetic findings associated with BD and response to mood stabilizers.

Methods: We searched PubMed, and Embase databases and classified the articles depending on the epigenetic mechanisms (DNA methylation, histone modifications and non-coding RNAs).

Results: We present the different epigenetic modifications associated with BD or with mood-stabilizers. The major reported mechanisms were DNA methylation, histone methylation and acetylation, and non-coding RNAs. Overall, the assessments are poorly harmonized and the results are more limited than in other psychiatric disorders (e.g. schizophrenia). However, the nature of BD and its treatment offer excellent opportunities for epigenetic research: clear impact of environmental factors, clinical variation between manic or depressive episodes resulting in possible identification of state and traits biomarkers, documented impact of mood-stabilizers on the epigenome.

Conclusion: Epigenetic is a growing and promising field in BD that may shed light on its pathophysiology or be useful as biomarkers of response to mood-stabilizer.
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http://dx.doi.org/10.1097/YPG.0000000000000267DOI Listing
February 2021

Editorial: Psychoneuroendocrinology of Psychosis Disorders.

Front Psychiatry 2020 9;11:607590. Epub 2020 Nov 9.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.3389/fpsyt.2020.607590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680761PMC
November 2020

Review and Consensus on Pharmacogenomic Testing in Psychiatry.

Pharmacopsychiatry 2021 Jan 4;54(1):5-17. Epub 2020 Nov 4.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City and School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (), oxcarbazepine (), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes () is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.
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http://dx.doi.org/10.1055/a-1288-1061DOI Listing
January 2021

Use of Prazosin for Pediatric Post-Traumatic Stress Disorder With Nightmares and/or Sleep Disorder: Case Series of 18 Patients Prospectively Assessed.

Front Psychiatry 2020 22;11:724. Epub 2020 Jul 22.

Child and Adolescent Psychiatric Unit, URHEA, CHSR Sotteville les Rouen, Rouen, France.

Objectives: Few studies have investigated pharmacologic treatment for pediatric post-traumatic stress disorder (PTSD). Prazosin, an alpha-1 adrenergic receptor antagonist, has been studied and demonstrated to be efficacious in an adult population for PTSD related sleep disturbances; however, in the pediatric population, data is limited to case reports and retrospective case series. This study prospectively assessed the safety and effects of Prazosin on PTSD symptoms in a pediatric sample.

Methods: Since 2016, 18 patients with PSTD under the age of 15 admitted in a child and adolescent psychiatric unit were challenged with prazosin as part of a treatment protocol. PTSD symptoms and adverse effects were collected weekly and prospectively assessed each month with validated clinical scales. All data were retrospectively analyzed. This treatment protocol and the evaluation of clinical data were approved by our Ethical committee for research on preexisting data at the University Teaching Hospital of Rouen.

Results: Among the 18 patients (10 girls and 8 boys), 13 (72%) had experienced sexual abuse and 5 (28%) family violence. After 1 month of treatment with a mean prazosin dose of 2.16 ( ± 0.6) mg/day, the CGI-S score significantly decreased from 5.3 ( ± 0.9) to 2.9 ( ± 0.7) (improvement of 43%). The mean total UCLA-PTSD-RI score significantly decreased 11.4 points ( ± 5.4) during the first week and 37.9 ( ± 16) during the first month, leading to an improvement of 20% and 67%, respectively. The improvement was significant irrespective of trauma exposure or sex. No adverse effects were reported except for one patient (hypotension).

Conclusion: Consistent with prior case reports and retrospective reviews, our retrospective analysis of data prospectively and systematically assessed among 18 patients suggests that prazosin is well-tolerated and associated with improvement in symptoms for pediatric PTSD.
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http://dx.doi.org/10.3389/fpsyt.2020.00724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388897PMC
July 2020

Stress, Cortisol and NR3C1 in At-Risk Individuals for Psychosis: A Mendelian Randomization Study.

Front Psychiatry 2020 10;11:680. Epub 2020 Jul 10.

Institut de Psychiatrie et Neurosciences de Paris, INSERM UMR 1266, Laboratoire de Physiopathologie des Maladies Psychiatriques, Université de Paris, GDR3557-Institut de Psychiatrie, Paris, France.

Introduction: The emergence of psychosis in at-risk individuals results from interactions between genetic vulnerability and environmental factors, possibly involving dysregulation of the hypothalamic-pituitary-adrenal axis. Hypercorticism was indeed described in schizophrenia and ultra-high-risk states, but its association with clinical outcome has yet to be demonstrated. The impact of stress through cortisol may vary depending on the expression level of genes related to the stress pathway.

Methods: To test this hypothesis, we selected , the gene encoding the glucocorticoid receptor, and modeled through logistic regression how its peripheral expression could explain some of the risk of psychosis, independently of peripheral cortisol levels, in a French longitudinal prospective cohort of 133 at-risk individuals, adjusted for sex, age, cannabis, and antipsychotic medication intake. We then performed a genome-wide association analysis, stratified by sex (55 females and 78 males), to identify expression quantitative trait loci to be used as instrumental variables in a Mendelian randomization framework.

Results: expression was significantly associated with a higher risk of conversion to psychosis (OR = 2.03, p = 0.03), independently of any other factor. Cortisol was not associated with outcome nor correlated with . In the female subgroup, rs6849528 was associated both with mRNA levels (p = 0.015, Effect-Size = 2.7) and conversion (OR = 8.24, p = 0.03).

Conclusions: For the same level of cortisol, expression increases psychotic risk, independently of sex, age, cannabis, and antipsychotic intake. In females, Mendelian randomization confirmed 's effect on outcome to be unbiased by any environmental confounder.
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http://dx.doi.org/10.3389/fpsyt.2020.00680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367416PMC
July 2020

A polymorphism in the glutamate metabotropic receptor 7 is associated with cognitive deficits in the early phases of psychosis.

Schizophr Res 2020 Jul 2. Epub 2020 Jul 2.

Department of Psychiatry, McGill University, Montreal, Quebec, Canada; Douglas Mental Health University Institute, Montreal, Quebec, Canada.

Schizophrenia is an illness characterized by positive symptoms, negative symptoms, and cognitive impairments. Cognitive impairments occur before the onset of psychosis and could reflect glutamatergic dysregulation. Thus, identifying associations between genetic variations in genes coding for glutamatergic receptors and cognitive impairment in schizophrenia may help in understanding the basis of these deficits and in identifying potential drug targets. In a discovery cohort of 144 first-episode of psychosis patients (FEP), we genotyped 58 candidate Single Nucleotide Polymorphisms (SNPs) located in NMDA and metabotropic glutamatergic receptors. These SNPs were selected according to the results from the Psychiatric Genomic Consortium and were tested for association with intellectual quotient (IQ) as assessed with the Wechsler Intelligence Scales. For replication, we used the ICAAR cohort including 121 ultra-high-risk patients (UHR) with the same cognitive assessment. A polymorphism located in GRM7, rs1396409, was significantly associated with performance IQ in the discovery cohort of FEP. This association was replicated in the UHR cohort. This polymorphism is also associated with total IQ and verbal IQ in the merged dataset, with a predominant effect on the arithmetic subtest. The rs1396409 polymorphism is significantly associated with cognitive impairment during the onset of psychosis. This genetic association highlights the possible impact of glutamatergic genes in cognitive deficits in the early phases of psychosis and enforces the interest for new therapeutic interventions targeting the glutamatergic pathway.
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http://dx.doi.org/10.1016/j.schres.2020.06.019DOI Listing
July 2020

Dysregulation of peripheral expression of the YWHA genes during conversion to psychosis.

Sci Rep 2020 06 17;10(1):9863. Epub 2020 Jun 17.

Université de Paris, Institut of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, team Physiopathologie des Maladies Psychiatriques, GDR3557-Institut de Psychiatrie, Paris, France.

The seven human 14-3-3 proteins are encoded by the YWHA-gene family. They are expressed in the brain where they play multiple roles including the modulation of synaptic plasticity and neuronal development. Previous studies have provided arguments for their involvement in schizophrenia, but their role during disease onset is unknown. We explored the peripheral-blood expression level of the seven YWHA genes in 92 young individuals at ultra-high risk for psychosis (UHR). During the study, 36 participants converted to psychosis (converters) while 56 did not (non-converters). YWHA genes expression was evaluated at baseline and after a mean follow-up of 10.3 months using multiplex quantitative PCR. Compared with non-converters, the converters had a significantly higher baseline expression levels for 5 YWHA family genes, and significantly different longitudinal changes in the expression of YWHAE, YWHAG, YWHAH, YWHAS and YWAHZ. A principal-component analysis also indicated that the YWHA expression was significantly different between converters and non-converters suggesting a dysregulation of the YWHA co-expression network. Although these results were obtained from peripheral blood which indirectly reflects brain chemistry, they indicate that this gene family may play a role in psychosis onset, opening the way to the identification of prognostic biomarkers or new drug targets.
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http://dx.doi.org/10.1038/s41598-020-66901-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299951PMC
June 2020

Reliability and correlation of mixture cell correction in methylomic and transcriptomic blood data.

BMC Res Notes 2020 Feb 12;13(1):74. Epub 2020 Feb 12.

Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, 102-108 Rue de la Santé, 75014, Paris, France.

Objectives: The number of DNA methylome and RNA transcriptome studies is growing, but investigators have to consider the cell type composition of tissues used. In blood samples, the data reflect the picture of a mixture of different cells. Specialized algorithms can address the cell-type heterogeneity issue. We tested if these corrections are correlated between two heterogeneous datasets.

Results: We used methylome and transcriptome datasets derived from a cohort of ten individuals whose blood was sampled at two different timepoints. We examined how the cell composition derived from these omics correlated with each other using "CIBERSORT" for the transcriptome and "estimateCellCounts function" in R for the methylome. The correlation coefficients between the two omic datasets ranged from 0.45 to 0.81 but correlations were minimal between two different timepoints. Our results suggest that a posteriori correction of a mixture of cells present in blood samples is reliable. Using an omic dataset to correct a second dataset for relative fractions of cells appears to be applicable, but only when the samples are simultaneously collected. This could be beneficial when there are difficulties to control the cell types in the second dataset, even when the sample size is limited.
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http://dx.doi.org/10.1186/s13104-020-4936-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017605PMC
February 2020

Transdifferentiation of Human Circulating Monocytes Into Neuronal-Like Cells in 20 Days and Without Reprograming.

Front Mol Neurosci 2018 19;11:323. Epub 2018 Sep 19.

INSERM U1016, Institut Cochin, Paris, France.

Despite progress, our understanding of psychiatric and neurological illnesses remains poor, at least in part due to the inability to access neurons directly from patients. Currently, there are models available but significant work remains, including the search for a less invasive, inexpensive and rapid method to obtain neuronal-like cells with the capacity to deliver reproducible results. Here, we present a new protocol to transdifferentiate human circulating monocytes into neuronal-like cells in 20 days and without the need for viral insertion or reprograming. We have thoroughly characterized these monocyte-derived-neuronal-like cells (MDNCs) through various approaches including immunofluorescence (IF), flow cytometry, qRT-PCR, single cell mRNA sequencing, electrophysiology and pharmacological techniques. These MDNCs resembled human neurons early in development, expressed a variety of neuroprogenitor and neuronal genes as well as several neuroprogenitor and neuronal proteins and also presented electrical activity. In addition, when these neuronal-like cells were exposed to either dopamine or colchicine, they responded similarly to neurons by retracting their neuronal arborizations. More importantly, MDNCs exhibited reproducible differentiation rates, arborizations and expression of dopamine 1 receptors (DR1) on separate sequential samples from the same individual. Differentiation efficiency measured by cell morphology was on average 11.9 ± 1.4% (mean, SEM, = 38,819 cells from 15 donors). To provide context and help researchers decide which model of neuronal development is best suited to address their scientific question,we compared our results with those of other models currently available and exposed advantages and disadvantages of each paradigm.
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http://dx.doi.org/10.3389/fnmol.2018.00323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156467PMC
September 2018

Lithium improved behavioral and epileptic symptoms in an adolescent with ring chromosome 20 and bipolar disorder not otherwise specified.

Clin Case Rep 2018 Nov 12;6(11):2234-2239. Epub 2018 Oct 12.

URHEA Child and Adolescent Psychiatry Intensive Care Unit Centre Hospitalier du Rouvray Sottevile les Rouen France.

We present a case of ring chromosome 20 syndrome in a twelve-year-old girl, with resistant epileptic disease and severe behavioral impairment that both drastically improved after a lithium challenge. If replicated, this could support the use of lithium as a safe treatment in the management of this severe phenotype.
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http://dx.doi.org/10.1002/ccr3.1796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230629PMC
November 2018

Burnout in medical students before residency: A systematic review and meta-analysis.

Eur Psychiatry 2019 01 29;55:36-42. Epub 2018 Oct 29.

Inserm U894, Centre de Psychiatrie et Neurosciences, Paris, France; CNRS GDR 3557 Institut de psychiatrie, France; Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. Electronic address:

Background: Applying the concept of burnout to medical students before residency is relatively recent. Its estimated prevalence varies significantly between studies. Our objective was to estimate the prevalence of burnout in medical students worldwide.

Methods: We systematically searched Medline for English-language articles published between January 1, 2010 and December 31, 2017. We selected all the original studies about the prevalence of burnout in medical students before residency, using validated questionnaires for burnout. Statistical analyses were conducted using the OpenMetaAnalyst software.

Results: Prevalence of current burnout was extracted from 24 studies encompassing 17,431 medical students. Among them, 8060 suffered from burnout and we estimated the prevalence to be 44.2% [33.4%-55.0%]. The information about the prevalence of each subset of burnout dimensions was given in nine studies including 7588 students. Current prevalence was estimated to be 40.8% for 'emotional exhaustion' [32.8%-48.9%], 35.1% [27.2%-43.0%] for 'depersonalization' and 27.4% [20.5%-34.3%] for 'personal accomplishment'. There is no significant gender difference in burnout. The prevalence of burnout is slightly different across countries with a higher prevalence in Oceania and the Middle East than in other continents.

Conclusions: The results of this meta-analysis suggest that one student out of two is suffering from burnout, even before residency. Again, our findings highlight the high level of distress in the medical population. These results should encourage the development of preventive strategies.
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http://dx.doi.org/10.1016/j.eurpsy.2018.08.006DOI Listing
January 2019

Exome sequencing of sporadic childhood-onset schizophrenia suggests the contribution of X-linked genes in males.

Am J Med Genet B Neuropsychiatr Genet 2019 09 30;180(6):335-340. Epub 2018 Oct 30.

Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal abnormalities, and the contribution of other forms of genetic variations remains unestablished. Using a whole-exome sequencing approach, we examined 12 COS trios where the unaffected parents had an affected male child. The sequencing data enabled us to test if the hemizygous variants, transmitted from the unaffected carrying mother, could mediate the phenotype (X-linked recessive inheritance model). Our results revealed that affected children have a significantly greater number of X-linked rare variants than their unaffected fathers. The variants identified in the male probands were mostly found in genes previously linked to other neuropsychiatric diseases like autism, intellectual disability, and epilepsy, including LUZP4, PCDH19, RPS6KA3, and OPHN1. The level of expression of the genes was assessed at different developmental periods in normal brain using the BrainSpan database. This approach revealed that some of them were expressed earlier in males than in females, consistent with the younger age of onset in male COS. In conclusion, this article suggests that X-linked genes might play a role in the pathophysiology of COS. Candidate genes detailed here could explain the higher level of comorbidities and the earlier age of onset observed in a subset of the male COS cases.
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http://dx.doi.org/10.1002/ajmg.b.32683DOI Listing
September 2019

New synthetic opioids: Part of a new addiction landscape.

Neurosci Biobehav Rev 2019 11 12;106:133-140. Epub 2018 Sep 12.

Addiction Research and Treatment Center, Paul Brousse Hospital, Paris-Sud University, CESP, Villejuif, France.

Synthetic opioids (SO) are a major risk for public health across the world. These drugs can be divided into 2 categories, pharmaceutical and non-pharmaceutical fentanyls. A new generation of SO has emerged on the drug market since 2010. North America is currently facing an opioid epidemic of morbi-mortality, caused by over-prescription of opioids, illegally diverted prescribed medicines, the increasing use of heroin and the emergence of SO. Furthermore, this opioid crisis is also seen in Europe. SO are new psychoactive substances characterized by different feature such as easy availability on the Internet, low price, purity, legality, and lack of detection in laboratory tests. They have not been approved or are not recommended for human use. Opioid misuse is associated with somatic and psychiatric complications. For many substances, limited pharmacological information is available, increasing the risk of harmful adverse events. Health actors and the general population need to be clearly informed of the potential risks and consequences of the diffusion and use of SO.
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http://dx.doi.org/10.1016/j.neubiorev.2018.06.010DOI Listing
November 2019

Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia.

Mol Psychiatry 2020 04 12;25(4):821-830. Epub 2018 Jun 12.

Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium-potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified. This led to the identification of a third case with a possibly damaging missense mutation in ATP1A3 and three others cases with predicted pathogenic missense variants in the FXYD gene family (FXYD1, FXYD6, and FXYD6-FXYD2 readthrough). FXYD genes encode proteins that modulate the ATP-dependant pump function. This report is the first to identify variants in the same pathway for COS. Our COS study illustrates the interest of stratifying a complex condition according to the age of onset for the identification of deleterious variants. Whereas ATP1A3 is a replicated gene in rare neuropediatric diseases, this gene has previously been linked with COS in only one case report. The association with rare variants in FXYD gene family is novel and highlights the interest of exploring these genes in COS as well as in pediatric neurodevelopmental disorders.
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http://dx.doi.org/10.1038/s41380-018-0103-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291354PMC
April 2020

Epigenetic variability in conversion to psychosis: novel findings from an innovative longitudinal methylomic analysis.

Transl Psychiatry 2018 04 26;8(1):93. Epub 2018 Apr 26.

Centre de Psychiatrie et Neurosciences, Université Paris Descartes, PRES Université Paris Sorbonne Paris Cité, UMR S 894, Paris, France.

Conversion to psychosis is a longitudinal process during which several epigenetic changes have been described. We tested the hypothesis that epigenetic variability in the methylomes of ultra-high risk (UHR) individuals may contribute to the risk of conversion. We studied a longitudinal cohort of UHR individuals (n = 39) and compared two groups (converters, n = 14 vs. non-converters, n = 25). A longitudinal methylomic study was conducted using Infinium HumanMethylation450 BeadChip covering half a million cytosine-phosphate-guanine (CpG) sites across the human genome from whole-blood samples. We used two statistical methods to investigate the variability of methylation probes. (i) The search for longitudinal variable methylation probes (VMPs) based on median comparisons identified two VMPs in converters only. The first CpG was located in the MACROD2 gene and the second CpG was in an intergenic region at 8q24.21. (ii) The detection of outliers using variance analysis related to private epimutations identified a dozen CpGs in converters only and highlighted two genes (RAC1 and SPHK1) from the sphingolipid signaling pathway. Our study is the first to support increased methylome variability during conversion to psychosis. We speculate that stochastic factors could increase DNA methylation variability and have a role in the complex pathophysiology of conversion to psychosis as well as in other psychiatric diseases.
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http://dx.doi.org/10.1038/s41398-018-0138-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916914PMC
April 2018

Longitudinal Analyses of Blood Transcriptome During Conversion to Psychosis.

Schizophr Bull 2019 01;45(1):247-255

Universite Paris Descartes, Université Sorbonne Paris Cite, Paris, France.

The biological processes associated with the onset of schizophrenia remain largely unknown. Current hypotheses favor gene × environment interactions as supported by our recent report about DNA methylation changes during the onset of psychosis. Here, we conducted the first longitudinal transcriptomic analysis of blood samples from 31 at-risk individuals who later converted to psychosis and 63 at-risk individuals who did not. Individuals were followed for a maximum of 1 year. Blood samples were collected at baseline and at the end of follow-up and individuals served as their own controls. Differentially expressed genes between the 2 groups were identified using the RNA sequencing of an initial discovery subgroup (n = 15 individuals). The most promising results were replicated using high-throughput real-time qPCR in the whole cohort (n = 94 individuals). We identified longitudinal changes in 4 brain-expressed genes based on RNAseq analysis. One of these genes (CPT1A) was replicated in the whole cohort. The previously observed hypermethylation in NRP1 and GSTM5 during the onset of psychosis correlated with a decrease in corresponding gene expression. RNA sequencing also identified 2 co-expression networks that were impaired after conversion compared with baseline-the Wnt pathway including AKT1, CPT1A and semaphorins, and the Toll-like receptor pathway, related to innate immunity. This longitudinal study of transcriptomic changes in individuals with at-risk mental state revealed alterations during conversion to psychosis in pathways and genes relevant to schizophrenia. These results may be a first step toward better understanding psychosis onset. They may also help to identify new biomarkers and targets for disease-modifying therapeutic strategies.
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http://dx.doi.org/10.1093/schbul/sby009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293211PMC
January 2019

Diagnostic approach to neurotransmitter monoamine disorders: experience from clinical, biochemical, and genetic profiles.

J Inherit Metab Dis 2018 01 18;41(1):129-139. Epub 2017 Sep 18.

Metabolomic and proteomic Biochemical department, Necker Enfants-Malades Hospital, Paris Descartes University, Paris, France.

Background And Aim: To improve the diagnostic work-up of patients with diverse neurological diseases, we have elaborated specific clinical and CSF neurotransmitter patterns.

Methods: Neurotransmitter determinations in CSF from 1200 patients revealed abnormal values in 228 (19%) cases. In 54/228 (24%) patients, a final diagnosis was identified.

Results: We have reported primary (30/54, 56%) and secondary (24/54, 44%) monoamine neurotransmitter disorders. For primary deficiencies, the most frequently mutated gene was DDC (n = 9), and the others included PAH with neuropsychiatric features (n = 4), PTS (n = 5), QDPR (n = 3), SR (n = 1), and TH (n = 1). We have also identified mutations in SLC6A3, FOXG1 (n = 1 of each), MTHFR (n = 3), FOLR1, and MTHFD (n = 1 of each), for dopamine transporter, neuronal development, and folate metabolism disorders, respectively. For secondary deficiencies, we have identified POLG (n = 3), ACSF3 (n = 1), NFU1, and SDHD (n = 1 of each), playing a role in mitochondrial function. Other mutated genes included: ADAR, RNASEH2B, RNASET2, SLC7A2-IT1 A/B lncRNA, and EXOSC3 involved in nuclear and cytoplasmic metabolism; RanBP2 and CASK implicated in post-traductional and scaffolding modifications; SLC6A19 regulating amino acid transport; MTM1, KCNQ2 (n = 2), and ATP1A3 playing a role in nerve cell electrophysiological state. Chromosome abnormalities, del(8)(p23)/dup(12) (p23) (n = 1), del(6)(q21) (n = 1), dup(17)(p13.3) (n = 1), and non-genetic etiologies (n = 3) were also identified.

Conclusion: We have classified the final 54 diagnoses in 11 distinctive biochemical profiles and described them through 20 clinical features. To identify the specific molecular cause of abnormal NT profiles, (targeted) genomics might be used, to improve diagnosis and allow early treatment of complex and rare neurological genetic diseases.
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http://dx.doi.org/10.1007/s10545-017-0079-6DOI Listing
January 2018

ABCB1 C3435T polymorphism is associated with tetrahydrocannabinol blood levels in heavy cannabis users.

Psychiatry Res 2018 Apr 9;262:357-358. Epub 2017 Sep 9.

Paul Brousse Hospital, Department of Addictology and Psychiatry, Villejuif 94800, France; Université Paris-Sud, U1178, France; Inserm 1178, Paris, France.

ABCB1 polymorphisms are known to modify drug pharmacokinetics but have yet to be studied for their role in generating and maintaining cannabis dependence. The objective of this study is to determine if ABCB1 C3435T (rs1045642) polymorphism may modulate Δ9-Tetrahydrocannabinol (THC) blood levels in a sample of heavy cannabis users. The study sample includes 39 Caucasian individuals, recruited in two French addictology centres, with isolated cannabis dependence and heavy use (defined as ≥ 7 joints per week). Each underwent clinical evaluation, cannabis blood metabolite dosage (THC, 11-OH-THC, and THC-COOH) and genotyping of ABCB1 C3435T polymorphism. In this population (males: 74.4%, average age 29.5 +/- 9), average cannabis use was 21 joints per week (median 12; range 7 - 80). T carriers (TT/CT) had significantly lower plasma THC levels (ng/ml) versus non T carriers (8 vs 15.70, significant), controlling for level of weekly use, 11-OH-THC and THC-COOH levels. Our results show that ABCB1 C3435T polymorphism may modulate serum THC levels in chronic heavy cannabis users. The exact mechanisms and roles that this may play in cannabis dependence genesis and evolution remain to be elucidated. These results should be controlled in a replication study using a larger population.
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http://dx.doi.org/10.1016/j.psychres.2017.09.006DOI Listing
April 2018

[Genetics and epigenetics of schizophrenia and other psychoses].

Biol Aujourdhui 2017 6;211(1):69-82. Epub 2017 Jul 6.

INSERM, U894, Laboratoire "Physiopathologie des maladies psychiatriques", Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, 102-108 rue de la Santé, 75014 Paris, France Institut de Psychiatrie-GDR 3557, Centre Hospitalier Sainte-Anne, Paris, France.

Schizophrenia and other psychoses are categorical psychiatric diagnoses corresponding to frequent and heterogeneous disorders. Their physiopathology still remains largely unknown despite numerous recent advances. In particular, the last decade has identified different types of genetic variants, thanks to emergence of high-throughput methods. These methods allow both the identification of rare variants with a large effect such as punctual mutations or copy-number variants and the identification of frequent variants with a limited effect such as polymorphisms. Many impacted genes have been identified showing a very high genetic heterogeneity of psychoses. These genes are overrepresented in synaptic and neurotransmission pathways. Only a small fraction of psychoses could be easily explained by genetics but this screening in clinical practice is important as it can lead to therapeutic challenge or genetic counselling. Nowadays, it is clear that the pathophysiology of the psychoses can only be understood by an integrative approach taking into account the interaction between genes and environment. This interaction could be mediated by the epigenome defined as the modification of gene expression without changes in DNA sequence. Epigenome is stable but could be modified by environmental factors. Several epigenetic mechanisms have been studied in psychosis, in particular the DNA methylation, the modification of histones and the microRNA. All of these mechanisms are under regulation by genetic factors and variants in these epigenetic-involved genes and cofactors have been also associated with schizophrenia. Thus, pathophysiology of psychosis is complex and morestudiesare needed before definitive conclusions. Altogether, the recent advances in the genetics and epigenetics of psychosis are promising and could open the way to a recategorization of these disorders as well as the identification of new therapeutic targets.
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http://dx.doi.org/10.1051/jbio/2017015DOI Listing
April 2018

Methylomic changes in individuals with psychosis, prenatally exposed to endocrine disrupting compounds: Lessons from diethylstilbestrol.

PLoS One 2017 13;12(4):e0174783. Epub 2017 Apr 13.

Université Paris Descartes, Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.

Background: In the Western world, between 1940 and 1970, more than 2 million people were exposed in utero to diethylstilbestrol (DES). In exposed individuals, and in their descendants, adverse outcomes have been linked to such exposure, including cancers, genital malformations, and less consistently, psychiatric disorders. We aimed to explore whether prenatal DES exposure would be associated with DNA methylation changes, and whether these epigenetic modifications would be associated with increased risk of psychosis.

Methods: From 247 individuals born from mothers exposed to DES, we selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to DES. We performed a methylome-wide association study using HumanMethylation450 DNA Analysis BeadChip® in peripheral blood. We analyzed methylation changes at individual CpGs or regions in exposed (n = 37) versus unexposed individuals (n = 32). We also compared exposed individuals with (n = 7) and without psychosis (n = 30).

Results: There were more individuals with schizophrenia in the DES-exposed group. We found no significant differences between exposed and unexposed individuals with respect to differentially methylated CpGs or regions. The largest difference was in a region near the promoter of an ADAMTS proteoglycanase gene (ADAMTS9). Compared to exposed individuals without psychosis, exposed individuals with psychosis had differential methylation in the region encompassing the gene encoding the zinc finger protein 57 (ZFP57).

Conclusions: In utero exposure to DES was not associated with methylation changes at specific CpG or regions. In exposed individuals, however, psychosis was associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174783PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390994PMC
April 2017

Paradoxical Improvement of Schizophrenic Symptoms by a Dopaminergic Agonist: An Example of Personalized Psychiatry in a Copy Number Variation-Carrying Patient.

Biol Psychiatry 2016 08 8;80(4):e21-e23. Epub 2015 Oct 8.

Service Hospitalo Universitaire, Center for Cognitive Remediation and Rehabilitation, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Faculté de Médecine Paris Descartes, Paris, France; Center for Psychiatry and Neuroscience, Laboratory for Pathophysiology of Psychiatric Diseases-Institut de Psychiatrie, University Paris Descartes, Sorbonne Paris Cité, Inserm UMR 894, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2015.09.017DOI Listing
August 2016

Salivary cortisol in early psychosis: New findings and meta-analysis.

Psychoneuroendocrinology 2016 Jan 16;63:262-70. Epub 2015 Oct 16.

Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire-S14, Faculté de Médecine Paris Descartes, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; INSERM UMR 894, Centre de Psychiatrie et Neurosciences, Laboratoire de Physiopathologie des Maladies Psychiatriques, Institut de Psychiatrie-GDR 3557 de Psychiatrie, 75014 Paris, France. Electronic address:

Background: Schizophrenia is a multifactorial disorder and environmental risk factors for it might contribute to hypothalamo-pituitary-adrenal axis (HPA) dysregulation. While increased cortisol levels have been reported in schizophrenia, as well as in early psychosis (compared to healthy controls), a crucial unresolved issue is whether elevated cortisol levels could be related to the distress of an emerging illness, rather than being specific to psychosis. Here, we report new findings from the first French cohort of young help-seekers (ICAAR) including ultra-high risk subjects (UHR), first-episode of psychosis (FEP) and non at-risk help seekers controls (HSC), followed by a meta-analysis of all available reports on salivary basal cortisol levels in early psychosis (UHR and FEP).

Methods: In the ICAAR study, 169 individuals (15-30 years old) had their basal cortisol levels sampled and they were categorized (at baseline) as either UHR, FEP, or HSC using the criteria of the Comprehensive Assessment of At-Risk Mental States (CAARMS). The three groups were compared at baseline, and the UHR and HSC individuals were also included in a one-year longitudinal follow-up. UHRs who converted to psychosis at the follow up (UHR-P) were compared to non-converters (UHR-NP). We also performed a meta-analysis from case-control studies with basal salivary measures of cortisol, drawing from a systematic bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'schizotypal ', 'prodromal schizophrenia', 'first-episode psychosis', 'first episode schizophrenia', 'newly diagnosed schizophrenia', 'recent onset schizophrenia' [in Medline, Web of Knowledge (WOS), EBSCO], followed by a systematic screening of the resulting articles.

Results: Basal cortisol levels were not significantly different between UHR, FEP, and HSC controls in the ICAAR cohort. Interestingly, initial cortisol levels were correlated with positive symptoms at the one year follow-up in the ICAAR cohort. The meta-analysis revealed a significant elevation of the salivary basal cortisol levels in UHR individuals compared to controls (8 studies--1060 individuals), but not between FEP and controls (6 studies--441 individuals). Indirect comparison of salivary basal cortisol levels between UHR and FEP did not yield significant differences. Finally, no differences were detected between the baseline cortisol of UHR-P and UHR-NP (4 studies--301 individuals).

Conclusion: The meta-analysis (including new data) indicates that basal cortisol levels were increased in UHR compared to controls, but FEP levels were not different from UHR or controls. Many confounding factors could decrease the effect size in FEP especially medication intake. Taken together with our new results (which made use of help-seeker controls, and not merely healthy controls), the findings indicate that basal cortisol levels may not be a reliable biomarker for early psychosis. Further studies are needed to clarify the precise role of the HPA axis in psychotic conversion.
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http://dx.doi.org/10.1016/j.psyneuen.2015.10.007DOI Listing
January 2016

Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia.

Schizophr Res 2014 Dec 18;160(1-3):97-103. Epub 2014 Oct 18.

Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Service Hospitalo-Universitaire, Centre Hospitalier Sainte-Anne, Paris, France; INSERM, U894, Laboratory "Pathophysiology of Psychiatric Disorders", Centre of Psychiatry and Neurosciences, Paris, France; Institut de Psychiatrie-GDR 3557 de Psychiatrie, France. Electronic address:

Background: Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia.

Methods: A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions.

Results: In the exploratory study, ten markers were in significant association with schizophrenia (P<0.01). One maker rs14251 (HDAC3) was replicated (P=0.04) and remained significant in the whole sample (P=0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 (HDAC9), rs7290710 (HDAC10) and rs7634112 (HDAC11) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia.

Conclusion: This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9, HDAC10, and HDAC11 was detected and seems biologically plausible.
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http://dx.doi.org/10.1016/j.schres.2014.09.029DOI Listing
December 2014

Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification.

Brain 2013 Nov 24;136(Pt 11):3395-407. Epub 2013 Sep 24.

1 Inserm U1079, Rouen, France.

Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40-60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 ± 20 years; mean age at last evaluation: 55 ± 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater in SLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don't reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression.
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http://dx.doi.org/10.1093/brain/awt255DOI Listing
November 2013

Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila.

Hum Mol Genet 2007 Mar 19;16(5):555-66. Epub 2007 Feb 19.

Inserm U614 (IFRMP), University of Rouen & Department of Genetics, Rouen University Hospital, Institute for Biomedical Research, Rouen, France.

Tauopathies, including Alzheimer's disease and fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), are a group of neurodegenerative disorders characterized by the presence of intraneuronal filamentous inclusions of aberrantly phosphorylated-tau. Tau is a neuronal microtubule-associated protein involved in microtubule assembly and stabilization. Currently, the molecular mechanisms underlying tau-mediated cellular toxicity remain elusive. To address the determinants of tau neurotoxicity, we first characterized the cellular alterations resulting from the over-expression of a mutant form of human tau associated with FTDP-17 (tau V337M) in Drosophila. We found that the over-expression of tau V337M, in Drosophila larval motor neurons, induced disruption of the microtubular network at presynaptic nerve terminals and changes in neuromuscular junctions morphological features. Secondly, we performed a misexpression screen to identify genetic modifiers of the tau V337M-mediated rough eye phenotype. The screening of 1250 mutant Drosophila lines allowed us to identify several components of the cytoskeleton, and particularly from the actin network, as specific modifiers of tau V337M-induced neurodegeneration. Furthermore, we found that numerous tau modulators identified in our screen were involved in the maintenance of synaptic function. Taken together, these findings suggest that disruption of the microtubule network in presynaptic nerve terminals could constitute early events in the pathological process leading to synaptic dysfunction in tau V337M pathology.
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http://dx.doi.org/10.1093/hmg/ddm011DOI Listing
March 2007
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