Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder.: HERV-W in schizophrenia and bipolar disorder

International audienceEpidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations

Defining bipolar mood states with quantitative measurement of inhibition/activation and emotional reactivity.

International audienceThe MATHYS scale, providing a score for inhibition/activation process and a score for emotional reactivity, is clearly useful to distinguish bipolar depressive episodes without manic symptoms from those with manic symptoms. This last type of depression appears to belong to a broad spectrum of mixed state. To go further we need to explore if these two types of depression are underlined by different mechanisms and what is the most appropriate treatment for each of them

Numerical investigation of combined buoyancy-thermocapillary convection and entropy generation in 3D cavity filled with Al2O3 nanofluid

Heat transfer, fluid flow and entropy generation due to combined buoyancy and thermocapillary forces in a 3D differentially heated enclosure containing Al2O3 nanofluid are carried out for different Marangoni numbers and different nanoparticles concentrations. The vector potential-vorticity formalism and the finite volume method are used respectively to formulate and to solve the governing equations and calculations were performed for Marangoni number from −103 to 103, volume fraction of nanoparticles from 0 to 0.2 and for a fixed Rayleigh number at 105. An intensification of the flow and an increase in heat transfer and of total entropy generation occur with the increase in nanoparticles volume fraction for all Marangoni numbers

A Comparison of Different Approaches to Clinical Phenotyping of Lithium Response: A Proof of Principle Study Employing Genetic Variants of Three Candidate Circadian Genes

International audienceOptimal classification of the response to lithium (Li) is crucial in genetic and biomarker research. This proof of concept study aims at exploring whether different approaches to phenotyping the response to Li may influence the likelihood of detecting associations between the response and genetic markers. We operationalized Li response phenotypes using the Retrospective Assessment of Response to Lithium Scale (i.e., the Alda scale) in a sample of 164 cases with bipolar disorder (BD). Three phenotypes were defined using the established approaches, whilst two phenotypes were generated by machine learning algorithms. We examined whether these five different Li response phenotypes showed different levels of statistically significant associations with polymorphisms of three candidate circadian genes (RORA, TIMELESS and PPARGC1A), which were selected for this study because they were plausibly linked with the response to Li. The three original and two revised Alda ratings showed low levels of discordance (misclassification rates: 8–12%). However, the significance of associations with circadian genes differed when examining previously recommended categorical and continuous phenotypes versus machine-learning derived phenotypes. Findings using machine learning approaches identified more putative signals of the Li response. Established approaches to Li response phenotyping are easy to use but may lead to a significant loss of data (excluding partial responders) due to recent attempts to improve the reliability of the original rating system. While machine learning approaches require additional modeling to generate Li response phenotypes, they may offer a more nuanced approach, which, in turn, would enhance the probability of identifying significant signals in genetic studies

Hostility and Trajectories of Body Mass Index Over 19 Years: The Whitehall II Study.

International audienceThe authors examined the associations of hostility measured in adulthood with subsequent body mass index (BMI; weight (kg)/height (m)(2)) assessed at 4 time points over a 19-year period (1985-2004) in a United Kingdom cohort study. A total of 6,484 participants (4,494 men and 1,990 women) aged 35-55 years at baseline (1985-1988) completed the Cook-Medley Hostility Scale. BMI was assessed upon medical examination in phases 1 (1985-1988), 3 (1991-1993), 5 (1997-1999), and 7 (2002-2004). Mixed-models analyses of repeated measures showed clear evidence of increasing BMI over follow-up in both sexes. In women, higher levels of hostility were associated with higher BMI at baseline, and this effect remained constant throughout the follow-up period. In men, hostility levels were also strongly associated with BMI at baseline, but results for the interaction between time and hostility also suggested that this association increased over time, with persons in the highest quartile of hostility gaining an excess of 0.016 units (P = 0.023) annually over the follow-up period as compared with persons in the lowest quartile. The authors conclude that the difference in BMI as a function of hostility levels in men is not stable over time

Production de savoirs à partir de données collectées par les associations de malades: L’exemple de la fibromyalgie

International audiencePour répondre au défi sociétal de démocratisation de l’accès à la connaissance, différentes initiatives de recherches participatives se développent : actions d’information, de formation ou de consultation des citoyens ou par l’intermédiaire de demandes de financement par des chercheurs auprès des associations. Cependant, peu des collaborations chercheurs-malades sont à l’initiative des personnes concernées, les patients et leurs familles. Nous avons adopté et testé cette démarche à la demande et en coopération avec l’association Fibromyalgie France

Sleep in remitted bipolar disorder: a naturalistic case-control study using actigraphy.

International audienceINTRODUCTION: Findings from actigraphic studies suggesting that sleep and circadian rhythms are disrupted in bipolar disorder (BD) patients have been undermined by methodological heterogeneity and the failure to adequately address potential confounders. METHOD: Twenty-six euthymic BD cases and 29 healthy controls (HC), recruited from University Paris-Est and matched for age and gender, were compared on subjective (Pittsburgh Sleep Questionnaire Inventory; PQSI) and objective (mean scores and variability in actigraphy) measures of sleep as recorded by over 21 consecutive days. RESULTS: Multivariate generalized linear modelling (GLM) revealed significant differences between BD cases and HC for five PSQI items (total score and four subscales), four actigraphy variables (mean scores) and five actigraphy variability measures. Backward stepwise linear regression (BSLR) indicated that a combination of four variables (mean sleep duration, mean sleep latency, variability of the fragmentation index over 21 days, and mean score on PSQI daytime dysfunction sub-scale) correctly classified 89% of study participants as cases or controls (Chi-square=39.81; df=6; p=0.001). LIMITATIONS: The sample size (although larger than most actigraphy studies) and incomplete matching of cases and controls may have influenced our findings. It was not possible to control for potential effects of psychotropic medication or differences in employment status between groups. CONCLUSIONS: When potential confounders of sleep and circadian profiles are adequately taken into account (particularly age, gender, daytime sleepiness, mood symptoms, body mass index, and risk of sleep apnoea), a selected subset of quantitative (mean scores) and qualitative (variability) features differentiated euthymic BD cases from HC