scholarly journals Dynamic expression of risk genes for schizophrenia and bipolar disorder across development

2018 ◽  
Author(s):  
Nicholas E Clifton ◽  
Eilís Hannon ◽  
Arianna Di Florio ◽  
Kerrie L Thomas ◽  
Peter A Holmans ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Prefrontal Cortex ◽  
Developmental Stages ◽  
Brain Regions ◽  
Risk Genes ◽  
Prefrontal Cortical ◽  
Expression Of Genes ◽  
Dynamic Expression ◽  
Genome Wide ◽  
And Control

ABSTRACTCommon genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between schizophrenia and bipolar disorder. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genes associated with schizophrenia have a strong bias towards increased expression in the prefrontal cortex during early midfetal development and early infancy, and decreased expression during late childhood which normalises in adolescence. Risk-associated genes for bipolar disorder shared this postnatal expression profile but did not exhibit a bias towards expression at any prenatal stage. These results emphasise the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the view that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.

A combined analysis of genome-wide expression profiling of bipolar disorder in human prefrontal cortex

2016 ◽  
Vol 82 ◽  
pp. 23-29 ◽  
Author(s):  
Jinglu Wang ◽  
Susu Qu ◽  
Weixiao Wang ◽  
Liyuan Guo ◽  
Kunlin Zhang ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Prefrontal Cortex ◽  
Expression Profiling ◽  
Combined Analysis ◽  
Genome Wide ◽  
Genome Wide Expression

scholarly journals Identification of a Risk Locus at 7p22.3 for Schizophrenia and Bipolar Disorder in East Asian Populations

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenqiang Li ◽  
Chu-Yi Zhang ◽  
Jiewei Liu ◽  
Fanglin Guan ◽  
Minglong Shao ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Whole Blood ◽  
Genome Wide Association Study ◽  
East Asian ◽  
Mrna Level ◽  
Risk Genes ◽  
Genome Wide ◽  
A Genome ◽  
Risk Snps ◽  
Risk Locus

Background: Shared psychopathological features and mechanisms have been observed between schizophrenia (SZ) and bipolar disorder (BD), but their common risk genes and full genetic architectures remain to be fully characterized. The genome-wide association study (GWAS) datasets offer the opportunity to explore this scientific question using combined genetic data from enormous samples, ultimately allowing a better understanding of the onset and development of these illnesses.Methods: We have herein performed a genome-wide meta-analysis in two GWAS datasets of SZ and BD respectively (24,600 cases and 40,012 controls in total, discovery sample), followed by replication analyses in an independent sample of 4,918 SZ cases and 5,506 controls of Han Chinese origin (replication sample). The risk SNPs were then explored for their correlations with mRNA expression of nearby genes in multiple expression quantitative trait loci (eQTL) datasets.Results: The single nucleotide polymorphisms (SNPs) rs1637749 and rs3800908 at 7p22.3 region were significant in both discovery and replication samples, and exhibited genome-wide significant associations when combining all East Asian SZ and BD samples (29,518 cases and 45,518 controls). The risk SNPs were also significant in GWAS of SZ and BD among Europeans. Both risk SNPs significantly predicted lower expression of MRM2 in the whole blood and brain samples in multiple datasets, which was consistent with its reduced mRNA level in the brains of SZ patients compared with normal controls. The risk SNPs were also associated with MAD1L1 expression in the whole blood sample.Discussion: We have identified a novel genome-wide risk locus associated with SZ and BD in East Asians, adding further support for the putative common genetic risk of the two illnesses. Our study also highlights the necessity and importance of mining public datasets to explore risk genes for complex psychiatric diseases.

Subtype transcriptomic profiling of myeloid cells in Alzheimer Disease brain illustrates the diversity in active microglia phenotypes

2021 ◽  
Author(s):  
Katherine E Prater ◽  
Kevin J. Green ◽  
Carole Smith ◽  
Wei Sun ◽  
Kenneth L. Chiou ◽  
...  
Keyword(s):  
Rational Design ◽  
Association Studies ◽  
Nucleic Acid Detection ◽  
Genome Wide Association Studies ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Dorsolateral Prefrontal ◽  
Health And Disease ◽  
Single Nucleus ◽  
And Control

Microglia-mediated neuroinflammation is hypothesized to contribute to disease progression in neurodegenerative diseases such as Alzheimer's Disease (AD). Microglia demonstrate heterogeneous states in health and disease, with proposed beneficial, harmful, and disease specific subtypes. Defining the spectrum of microglia phenotypes is an important step in rational design of neuroinflammation modulating therapies. To facilitate improved phenotype resolution and group comparisons based on disease state we performed single-nucleus RNA-seq on more than 120,000 microglia nuclei from AD and control dorsolateral prefrontal cortex. We identify clusters of microglia enriched for biological pathways implicating defined myeloid roles. We detected several previously unrecognized microglia populations in human AD brain, including three internalization and trafficking subtypes that were heterogeneous in their metabolic and inflammatory signatures. One of these endolysosomal subtypes is larger in AD individuals and was uniquely enriched for genes involved in nucleic acid detection and activation of interferon signaling. This inflammatory endolysosomal cluster also differentially regulated expression of genes associated with AD risk by genome wide association studies. We also identified a cluster of microglia with upregulated cell cycle and DNA repair genes that is proportionately larger in control individuals. Within cluster comparisons demonstrate that in AD brain, homeostatic microglia subpopulations upregulate inflammatory gene expression. These results highlight the heterogenous nature of the microglia response to AD pathology and will inform efforts to target specific subtypes of microglia in the development of novel AD therapies.

Prefrontal cortex activity in people with schizophrenia and control subjects

1998 ◽  
Vol 172 (4) ◽  
pp. 316-323 ◽  
Author(s):  
Sean A. Spence ◽  
Steven R. Hirsch ◽  
David J. Brooks ◽  
Paul M. Grasby
Keyword(s):  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Symptomatic Improvement ◽  
Emission Tomography ◽  
Cortical Function ◽  
Control Subjects ◽  
Prefrontal Cortical ◽  
Positron Emission ◽  
Dorsolateral Prefrontal ◽  
And Control

BackgroundHypo-activation of the left dorsolateral prefrontal cortex is inconsistently found in neuroimaging studies of schizophrenia. As the left dorsolateral prefrontal cortex is involved in the generation of action, disordered function in this region may be implicated in schizophrenic symptomatology.MethodWe used H215O positron emission tomography to study dorsolateral prefrontal cortical function in men with schizophrenia (n=13) and male control subjects (n=6) performing joystick movements on two occasions, 4–6 weeks apart. The patients were initially in relapse. To clarify dorsolateral prefrontal cortical function we also scanned another group of control subjects (n=5) performing mouth movements.ResultsThe control subjects performing hand or mouth movements activated the left dorsolateral prefrontal cortex to a maximum when the movements were self-selected. The men with relapsed schizophrenia exhibited left dorsolateral prefrontal cortical hypo-activation, which remitted with symptomatic improvement.ConclusionsHypofrontality in these patients is a dynamic phenomenon across time, possibly related to current symptomatology. The most appropriate question about the presence of hypofrontality in schizophrenia may be when, rather than whether, it will occur.

scholarly journals Dynamic shifts of visual and saccadic signals in prefrontal cortical regions 8Ar and FEF

2019 ◽  
Author(s):  
Sanjeev B. Khanna ◽  
Jonathan A. Scott ◽  
Matthew A. Smith
Keyword(s):  
Working Memory ◽  
Prefrontal Cortex ◽  
Spatial Working Memory ◽  
Active Vision ◽  
Brain Regions ◽  
Motor Tasks ◽  
Prefrontal Cortical ◽  
Spatial Registration ◽  
Cortical Regions ◽  
Spatial Locations

AbstractActive vision is a fundamental process by which primates gather information about the external world. Multiple brain regions have been studied in the context of simple active vision tasks in which a visual target’s appearance is temporally separated from saccade execution. Most neurons have tight spatial registration between visual and saccadic signals, and in areas such as prefrontal cortex (PFC) some neurons show persistent delay activity that links visual and motor epochs and has been proposed as a basis for spatial working memory. Many PFC neurons also show rich dynamics, which have been attributed to alternative working memory codes and the representation of other task variables. Our study investigated the transition between processing a visual stimulus and generating an eye movement in populations of PFC neurons in macaque monkeys performing a memory guided saccade task. We found that neurons in two subregions of PFC, the frontal eye fields (FEF) and area 8Ar, differed in their dynamics and spatial response profiles. These dynamics could be attributed largely to shifts in the spatial profile of visual and motor responses in individual neurons. This led to visual and motor codes for particular spatial locations that were instantiated by different mixtures of neurons, which could be important in PFC’s flexible role in multiple sensory, cognitive, and motor tasks.New and NoteworthyA central question in neuroscience is how the brain transitions from sensory representations to motor outputs. The prefrontal cortex contains neurons that have long been implicated as important in this transition and in working memory. We found evidence for rich and diverse tuning in these neurons, that was often spatially misaligned between visual and saccadic responses. This feature may play an important role in flexible working memory capabilities.

scholarly journals Altered expression of a unique set of genes reveals complex etiology of Schizophrenia

2017 ◽  
Author(s):  
Ashutosh Kumar ◽  
Himanshu Narayan Singh ◽  
Vikas Pareek ◽  
Khursheed Raza ◽  
Pavan Kumar ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Mrna Expression ◽  
Brain Regions ◽  
Contributing Factors ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Affy Package ◽  
Post Mortem Brain ◽  
A Genome ◽  
Neuronal Functions

AbstractPurposeThe etiology of schizophrenia is extensively debated, and multiple factors have been contended to be involved. A panoramic view of the contributing factors in a genome-wide study can be an effective strategy to provide a comprehensive understanding of its causality.Materials and MethodsGSE53987 dataset downloaded from GEO-database, which comprised mRNA expression data of post-mortem brain tissue across three regions from control and age-matched subjects of schizophrenia (N= Hippocampus (HIP): C-15, T-18, Prefrontal cortex (PFC): C-15, T-19, Associative striatum (STR): C-18, T-18). Bio-conductor-affy-package used to compute mRNA expression, and further t-test applied to investigate differential gene expression. The analysis of the derived genes performed using PANTHER Classification System and NCBI database.ResultsA set of 40 genes showed significantly altered (p<0.01) expression across all three brain regions. The analyses unraveled genes implicated in biological processes and events, and molecular pathways relating basic neuronal functions.ConclusionsThe deviant expression of genes maintaining basic cell machinery explains compromised neuronal processing in SCZ.AbbreviationsSchizophrenia (SCZ), Hippocampus (HIP), Associative striatum (STR), Prefrontal cortex (PFC)

scholarly journals Dynamic expression of genes associated with schizophrenia and bipolar disorder across development

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nicholas E. Clifton ◽  
Eilís Hannon ◽  
Janet C. Harwood ◽  
Arianna Di Florio ◽  
Kerrie L. Thomas ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Expression Of Genes ◽  
Dynamic Expression

scholarly journals A Combined Analysis of Genetically Correlated Traits Identifies Genes and Brain Regions for Insomnia

2020 ◽  
Vol 65 (12) ◽  
pp. 874-884
Author(s):  
Kezhi Liu ◽  
Ling Zhu ◽  
Minglan Yu ◽  
Xuemei Liang ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Genome Wide Association ◽  
Data Sets ◽  
Genome Wide Association Studies ◽  
New Genes ◽  
Genome Wide

Aims: Previous studies have inferred that there is a strong genetic component in insomnia. However, the etiology of insomnia is still unclear. This study systematically analyzed multiple genome-wide association study (GWAS) data sets with core human pathways and functional networks to detect potential gene pathways and networks associated with insomnia. Methods: We used a novel method, multitrait analysis of genome-wide association studies (MTAG), to combine 3 large GWASs of insomnia symptoms/complaints and sleep duration. The i-Gsea4GwasV2 and Reactome FI programs were used to analyze data from the result of MTAG analysis and the nominally significant pathways, respectively. Results: Through analyzing data sets using the MTAG program, our sample size increased from 113,006 subjects to 163,188 subjects. A total of 17 of 1,816 Reactome pathways were identified and showed to be associated with insomnia. We further revealed 11 interconnected functional and topologically interacting clusters (Clusters 0 to 10) that were associated with insomnia. Based on the brain transcriptome data, it was found that the genes in Cluster 4 were enriched for the transcriptional coexpression profile in the prenatal dorsolateral prefrontal cortex ( P = 7 × 10−5), inferolateral temporal cortex ( P = 0.02), medial prefrontal cortex ( P < 1 × 10−5), and amygdala ( P < 1 × 10−5), and detected RPA2, ORC6, PIAS3, and PRIM2 as core nodes in these 4 brain regions. Conclusions: The findings provided new genes, pathways, and brain regions to understand the pathology of insomnia.

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