Biology subjects

Tamouza, R.

Publications and source records attributed to Tamouza, R..

4 recordsLinked to original sources

bioRxiv2024

Deep analysis of the Major Histocompatibility Complex associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS

IntroductionWe have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC). MethodsA genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CTR) of European ancestry. 8 million single nucleotide polymorphisms (SNPs) and HLA class I and class II gene alleles were imputed to compare EC and CTR. Results2,626 SNPs were associated with EC (p<5.10-8), all located within the Major Histocompatibility Complex (MHC) region. Stepwise regression analysis narrowed this list to 17 SNPs. In parallel, 22 HLA class I and II alleles were associated with EC. Through meticulous mapping of the LD between all identified signals and employing reciprocal covariate analyses, we delineated a final set of 6 independent SNPs and 3 HLA class I gene alleles that accounted for most of the associations observed with EC. Our study revealed the presence of cumulative haploblock effects (SNP rs9264942 contributing to the HLA-B*57:01 effect) and that several HLA allele associations were in fact caused by SNPs in linkage disequilibrium (LD). Upon investigating SNPs in LD with the selected 6 SNPs and 3 HLA class I alleles for their impact on protein function (either damaging or differential expression), we identified several compelling mechanisms potentially explaining EC among which: a multi-action mechanism of HLA-B*57:01 involving MICA mutations and MICB differential expression overcoming the HIV-1 blockade of NK cell response, and overexpression of ZBTB12 with a possible anti-HIV-1 effect through HERV-K interference; a deleterious mutation in PPP1R18 favoring viral budding associated with rs1233396. ConclusionOur results show that MHC influence on EC likely extends beyond traditional HLA class I or class II allele associations, encompassing other MHC SNPs with various biological impacts. They point to the key role of NK cells in preventing HIV-1 infection. Our analysis shows that HLA-B*57:01 is indeed associated with a partially functional NK cell response which could also explain this markers involvement in other diseases such as psoriasis. More broadly, our findings suggest that within any HLA class I and II association in diseases, there may exist distinct causal SNPs within this crucial, gene-rich, and LD-rich MHC region.

immunology↗

bioRxiv2023

Mitochondrial Biomarkers and Metabolic Syndrome in Bipolar Disorder

ImportanceExamining translatable mitochondrial blood-based biological markers to identify its association with metabolic diseases in bipolar disorder. ObjectiveTo test whether mitochondrial metabolites, mainly lactate, and cell-free circulating mitochondrial DNA are associated with markers of metabolic syndrome in bipolar disorder, hypothesizing higher lactate but unchanged cell-free circulating mitochondrial DNA levels in bipolar disorder patients with metabolic syndrome. DesignIn a cohort study, primary testing from the FondaMental Advanced Centers of Expertise for bipolar disorder was conducted, including baseline plasma samples and blinded observers for all experimentation and analysis. SettingThe FondaMental Foundation coordinate a multicenter, multidisciplinary French networks aiming at creation of cohorts to improve identification of homogeneous subgroups of psychiatric disorders toward personalized treatments. ParticipantsThe FACE-BD primary testing cohort includes 837 stable bipolar disorder patients. The I-GIVE validation cohort consists of 235 participants: stable and acute bipolar patients, non-psychiatric controls, and acute schizophrenia patients. Participants were randomly selected based on biosample availability. ExposuresAll patients underwent the standard primary care within their center. No intentional exposures were part of this study. Main Outcome and MeasuresThe primary outcome modelled an association with lactate and metabolic syndrome in this population. Reflective a priori hypothesis. ResultsMultivariable regression analyses show lactate association with triglycerides (Est= 0.072(0.023), p = 0.0065,), fasting glucose (Est = 12(0.025), p= 0.000015) and systolic (Est= 0.003(0.0013), p= 0.031) and diastolic blood pressure (Est = 0.0095{+/-}0.0017, p= 1.3e-7). Significantly higher levels of lactate were associated with presence of metabolic syndrome (Est = 0.17{+/-}0.049, p=0.00061) after adjusting for potential confounding factors. Mitochondrial-targeted metabolomics identified distinct metabolite profiles in patients with lactate presence and metabolic syndrome, differing from those without lactate changes but with metabolic syndrome. Circulating cell-free mitochondrial DNA was not associated with metabolic syndrome. Conclusion & RelevanceThis thorough analysis mitochondrial biomarkers indicate the associations with lactate and metabolic syndrome, whereas circulating cell-free mitochondrial DNA is limited in the context of metabolic syndrome. This study is relevant to improve the identification and stratification of bipolar patients with metabolic syndrome and provide potential personalized-therapeutic opportunities. Key PointsO_ST_ABSQuestionC_ST_ABSCan lactate, a mitochondrial metabolite, indicate metabolic syndrome in bipolar disorder? FindingIn 837 stable bipolar disorder patients, we found high lactate levels significantly associated with metabolic syndrome, unlike circulating cell-free mitochondrial DNA. This pattern also appeared in acute bipolar and schizophrenia cases. Mitochondrial-targeted metabolomics distinguishes patients with high lactate and metabolic syndrome from those without lactate changes, but presence of metabolic syndrome. MeaningThis research underscores lactate as a potential biomarker for identifying bipolar disorder patients with metabolic syndrome. It opens new avenues for personalized treatment strategies, leveraging mitochondrial metabolite profiling to improve patient stratification and therapeutic outcomes.

neuroscience↗

bioRxiv2020

Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes

Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex (PFC). We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia, and shed light on the underlying cellular mechanisms.

neuroscience↗

bioRxiv2018

Increased and decreased superficial white matter structural connectivity in schizophrenia and bipolar disorder

Schizophrenia (SZ) and bipolar disorder (BD) are often conceptualized as \"disconnection syndromes\", with substantial evidence of abnormalities in deep white matter tracts, forming the substrates of long-range connectivity, seen in both disorders. However, the study of superficial white matter (SWM) U-shaped short-range tracts remained challenging until recently, although findings from post-mortem studies suggest they are likely integral components of SZ and BD neuropathology. This diffusion weighted imaging (DWI) study aimed to investigate SWM microstructure in vivo in both SZ and BD for the first time. We performed whole brain tractography in 31 people with SZ, 32 people with BD and 54 controls using BrainVISA and Connectomist 2.0. Segmentation and labelling of SWM tracts were performed using a novel, comprehensive U-fiber atlas. Analysis of covariances yielded significant generalized fractional anisotropy (gFA) differences for 17 SWM bundles in frontal, parietal and temporal cortices. Post hoc analyses showed gFA reductions in both patient groups as compared with controls in bundles connecting regions involved in language processing, mood regulation, working memory and motor function (pars opercularis, insula, anterior cingulate, precentral gyrus). We also found increased gFA in SZ patients in areas overlapping the default mode network (inferior parietal, middle temporal, precuneus), supporting functional hyperconnectivity of this network evidenced in SZ. We thus illustrate that short U-fibers are vulnerable to the pathological processes in major psychiatric illnesses, encouraging improved understanding of their anatomy and function.

neuroscience↗