Stem Cell Models for Context-Specific Modeling in Psychiatric Disorders

Seah, Carina; Huckins, Laura; Brennand, Kristen

doi:10.1016/j.biopsych.2022.09.033

Cited by 10 publications

(6 citation statements)

References 152 publications

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“…A key advantage of such a model system is the ability to combine the influences of genetic risk factors by using patient-derived hiPSCs with disease-relevant environmental exposures to gain better insight into the molecular mechanisms at play. Indeed, while stem cell-based models are used in psychiatric research, most of these studies primarily focus on neuronal cell types, leaving other cell types, including microglia, understudied [ 36 , 170 ].…”

Section: Introductionmentioning

confidence: 99%

Microglial contribution to the pathology of neurodevelopmental disorders in humans

Matuleviciute,

Akinluyi,

Muntslag

et al. 2023

Acta Neuropathol

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Microglia are the brain’s resident macrophages, which guide various developmental processes crucial for brain maturation, activity, and plasticity. Microglial progenitors enter the telencephalic wall by the 4th postconceptional week and colonise the fetal brain in a manner that spatiotemporally tracks key neurodevelopmental processes in humans. However, much of what we know about how microglia shape neurodevelopment comes from rodent studies. Multiple differences exist between human and rodent microglia warranting further focus on the human condition, particularly as microglia are emerging as critically involved in the pathological signature of various cognitive and neurodevelopmental disorders. In this article, we review the evidence supporting microglial involvement in basic neurodevelopmental processes by focusing on the human species. We next concur on the neuropathological evidence demonstrating whether and how microglia contribute to the aetiology of two neurodevelopmental disorders: autism spectrum conditions and schizophrenia. Next, we highlight how recent technologies have revolutionised our understanding of microglial biology with a focus on how these tools can help us elucidate at unprecedented resolution the links between microglia and neurodevelopmental disorders. We conclude by reviewing which current treatment approaches have shown most promise towards targeting microglia in neurodevelopmental disorders and suggest novel avenues for future consideration.

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Section: Introductionmentioning

confidence: 99%

Microglial contribution to the pathology of neurodevelopmental disorders in humans

Matuleviciute,

Akinluyi,

Muntslag

et al. 2023

Acta Neuropathol

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“…Our findings suggest that posttraumatic symptoms, when interacting with individual genetic variation, may play a role in the risk of developing somatic conditions, such as cardiometabolic, respiratory, or digestive conditions. These findings further prompt the critical need to identify transcriptional and cellular effects of genetic variants associated with PTSD through which they might be mediating risk to physical and somatic conditions. This study improves the understanding of psychiatric-somatic comorbidities by applying PGSs for psychiatric traits in EHRs, thus advancing the knowledge needed for precision diagnostics.…”

Section: Discussionmentioning

confidence: 99%

Genetic Liability to Posttraumatic Stress Disorder Symptoms and Its Association With Cardiometabolic and Respiratory Outcomes

Pathak,

Singh,

Choi

et al. 2024

JAMA Psychiatry

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ImportancePosttraumatic stress disorder (PTSD) has been reported to be a risk factor for several physical and somatic symptoms. However, the genetics of PTSD and its potential association with medical outcomes remain unclear.ObjectiveTo examine disease categories and laboratory tests from electronic health records (EHRs) that are associated with PTSD polygenic scores.Design, Setting, and ParticipantsThis genetic association study was conducted from July 15, 2021, to January 24, 2023, using EHR data from participants across 4 biobanks. The polygenic scores of PTSD symptom severity (PGS-PTSD) were tested with all available phecodes in Vanderbilt University Medical Center’s biobank (BioVU), Mass General Brigham (MGB), Michigan Genomics Initiative (MGI), and UK Biobank (UKBB). The significant medical outcomes were tested for overrepresented disease categories and subsequently tested for genetic correlation and 2-sample mendelian randomization (MR) to determine genetically informed associations. Multivariable MR was conducted to assess whether PTSD associations with health outcomes were independent of the genetic effect of body mass index and tobacco smoking.ExposuresPolygenic score of PTSD symptom severity.Main Outcomes and MeasuresA total of 1680 phecodes (ie, International Classification of Diseases, Ninth Revision– and Tenth Revision–based phenotypic definitions of health outcomes) across 4 biobanks and 490 laboratory tests across 2 biobanks (BioVU and MGB).ResultsIn this study including a total of 496 317 individuals (mean [SD] age, 56.8 [8.0] years; 263 048 female [53%]) across the 4 EHR sites, meta-analyzing associations of PGS-PTSD with 1680 phecodes from 496 317 individuals showed significant associations to be overrepresented from mental health disorders (fold enrichment = 3.15; P = 5.81 × 10−6), circulatory system (fold enrichment = 3.32; P = 6.39 × 10−12), digestive (fold enrichment = 2.42; P = 2.16 × 10−7), and respiratory outcomes (fold enrichment = 2.51; P = 8.28 × 10−5). The laboratory measures scan with PGS-PTSD in BioVU and MGB biobanks revealed top associations in metabolic and immune domains. MR identified genetic liability to PTSD symptom severity as an associated risk factor for 12 health outcomes, including alcoholism (β = 0.023; P = 1.49 × 10−4), tachycardia (β = 0.045; P = 8.30 × 10−5), cardiac dysrhythmias (β = 0.016, P = 3.09 × 10−5), and acute pancreatitis (β = 0.049, P = 4.48 × 10−4). Several of these associations were robust to genetic effects of body mass index and smoking. We observed a bidirectional association between PTSD symptoms and nonspecific chest pain and C-reactive protein.Conclusions and RelevanceResults of this study suggest the broad health repercussions associated with the genetic liability to PTSD across 4 biobanks. The circulatory and respiratory systems association was observed to be overrepresented in all 4 biobanks.

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“…Assessed in their natural contexts, the effects of genetic variants may have been confounded by other variants in high linkage disequilibrium, potentially obscuring true causal variants. Massively parallel reporter assays 104,105 (MPRAs) applied to assess allele-dependent transcriptional activity under glucocorticoid exposure contexts 106 could empirically resolve true causal variants underlying genotype-dependent stress encoding. Likewise, expansion of CRISPR screens of non-coding variants (e.g., CRISPR-QTL 107 ) and/or analysis of pools of dozens of donors (e.g., village-in-a-dish 108 ) may pinpoint putative enhancers with stress-dependent regulatory activity and reveal their downstream target genes.…”

Section: Discussionmentioning

confidence: 99%

Common genetic variation impacts stress response in the brain

Seah,

Signer,

Deans

et al. 2023

Preprint

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To explain why individuals exposed to identical stressors experience divergent clinical outcomes, we determine how molecular encoding of stress modifies genetic risk for brain disorders. Analysis of post-mortem brain (n=304) revealed 8557 stress-interactive expression quantitative trait loci (eQTLs) that dysregulate expression of 915 eGenes in response to stress, and lie in stress-related transcription factor binding sites. Response to stress is robust across experimental paradigms: up to 50% of stress-interactive eGenes validate in glucocorticoid treated hiPSC-derived neurons (n=39 donors). Stress-interactive eGenes show brain region- and cell type-specificity, and, in post-mortem brain, implicate glial and endothelial mechanisms. Stress dysregulates long-term expression of disorder risk genes in a genotype-dependent manner; stress-interactive transcriptomic imputation uncovered 139 novel genes conferring brain disorder risk only in the context of traumatic stress. Molecular stress-encoding explains individualized responses to traumatic stress; incorporating trauma into genomic studies of brain disorders is likely to improve diagnosis, prognosis, and drug discovery.Graphical Abstract

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Stem Cell Models for Context-Specific Modeling in Psychiatric Disorders

Cited by 10 publications

References 152 publications

Microglial contribution to the pathology of neurodevelopmental disorders in humans

Microglial contribution to the pathology of neurodevelopmental disorders in humans

Genetic Liability to Posttraumatic Stress Disorder Symptoms and Its Association With Cardiometabolic and Respiratory Outcomes

Common genetic variation impacts stress response in the brain

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