HLA genetics in bipolar disorder

Tamouza, Ryad; Oliveira, J.; Étain, Bruno; Bengoufa, Djaouïda; Hamdani, Nora; Manier, Céline; Mariaselvam, Christina Mary; Sundaresh, Aparna; Bellivier, Frank; Henry, Chantal; Jp, Kahn; Krishnamoorthy, Rajagopal; Charron, Dominique; Leboyer, Marion

doi:10.1111/acps.12912

Cited by 24 publications

(16 citation statements)

References 55 publications

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“…When GO:molecular function categories were analyzed in relation to the overlap with ASD SFARI genes, the "peptide antigen binding" category was found to be the most significant, which refers to the binding of peptides to MHC molecules. These results suggest that IFNγ signaling and the immune response may be relevant in the context of neurodevelopmental processes in BPI [61,62]. GO:localization analysis of genes shared between the DEGs and SCZ-associated genes showed the synapse to be the most significant category ( Table 4).…”

Section: Analysis Of Protein-protein Interaction (Ppi) Networkmentioning

confidence: 83%

“…Similarly, the GO and GSEA data implicate differences in BPI in processes involving the IFNγ signaling pathway, cytoskeletal binding proteins, cell adhesion molecules, LPS pathway, and GABAergic systems. The findings of immune system-related pathways as important in these ex vivo studies, including antigen processing via MHC, in the absence of any exogenous infectious or immune exposure in the experimental design is interesting since the MHC locus is one of the most significant loci for schizophrenia and also implicated in bipolar disorder [62,83]. We find it very interesting that the network analysis of our transcriptomic study and genes associated with BPI led to the identification of NCAN as a central hub for the differentially expressed genes.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

et al. 2020

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Background: Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with diseasespecific genetic backgrounds. Methods: Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays.Results: RNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER-mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids.Conclusions: Our studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission.

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Section: Analysis Of Protein-protein Interaction (Ppi) Networkmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

et al. 2020

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“…Another apparent paradigm of the implication of 8.1 AH not only in SZ but also in bipolar disorder (BD) deserves a mention. Indeed, analyzing the HLA haplotype diversity in BD, we recently observed that HLA‐8.1 AH‐derived haplotypes, namely HLA‐A*0201 ~ B*0801 ~ C*0701 and DRB1*301 ~ DQB1*201 were, respectively, associated with rapid cycling and suicidal behavior, two clinical presentations considered as proxy of disease severity and thought to be mediated by proinflammatory processes . Given the established shared genetic inheritance of SZ and BD, at least within the framework of immunogenetics, HLA‐associated immunogenetic processes may be at work with the 8.1 AH possibly contributing to neurodevelopmental specificities between these disorders.…”

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confidence: 99%

The HLA 8.1 ancestral haplotype in schizophrenia: dual implication in neuro‐synaptic pruning and autoimmunity?

Tamouza

Krishnamoorthy

Giegling

et al. 2020

Acta Psychiatr Scand

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“…Taken together, these findings suggest that IL-6, TNF-α, and progranulin may be biological markers common to both diseases. Genetic variations in HLA (human leukocyte antigen) genes have also been associated with both BD and FTD, and indicate that HLA-related inflammation mechanisms are also present in both disorders (Broce et al, 2018;Tamouza et al, 2018). Although we found shared inflammatory factors, Levels of neurotrophic factors have been less explored in peripheral tissue in FTD patients than inflammation markers.…”

Section: Bd Ftdmentioning

confidence: 55%

A review on shared clinical and biological aspects of bipolar disorder and frontotemporal dementia

Nascimento¹,

Villela²,

Rodriguez³

et al. 2018

Preprint

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Mental disorders are highly prevalent and important causes of medical burden worldwide. Co-occurrence of neurological and psychiatric symptoms are observed among mental disorders, representing a challenge for their differential diagnosis. Psychiatrists and neurologists have faced challenges in diagnosing older adults presenting behavioral changes. This is the case for early frontotemporal dementia (FTD) and late bipolar disorder. Early FTD is characterized by behavioral or language disturbances in the absence of cognitive symptoms. Consequently, patients with the behavioral subtype of FTD (bv-FTD) can be initially misdiagnosed as having a psychiatric disorder, typically depression or bipolar disorder (BD). Bipolar disorder is associated with a higher risk of dementia in older adults and cognitive impairment, where a subset of patients presents a neuroprogressive pattern during the disease course. Clinical similarities between BD and bv-FTD raise the question whether common molecular pathways might explain shared clinical symptoms. In fact, studies have also shown presence of molecular signatures related to bv-FTD in BD patients. Here, we reviewed existing data on clinical and molecular similarities between BD and FTD and propose biological pathways to be further investigated as common or specific markers of BD and FTD.

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HLA genetics in bipolar disorder

Abstract: Corroborating the established link between these HLA haplotypes/sub haplotypes and common immune disorders, our findings suggest possible HLA-mediated proinflammatory processes operating in BD.

Cited by 24 publications

References 55 publications

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

The HLA 8.1 ancestral haplotype in schizophrenia: dual implication in neuro‐synaptic pruning and autoimmunity?

A review on shared clinical and biological aspects of bipolar disorder and frontotemporal dementia

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