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Center for Common Disease Genomics [CCDG] - Neuropsychiatric: SPARK Simons Foundation Powering Autism Research for Knowledge

ABSTRACT: Center for Common Disease Genomics [CCDG] - Neuropsychiatric: SPARK Simons Foundation Powering Autism Research for Knowledge

PROVIDER: PRJNA749825 | ENA |

REPOSITORIES: ENA

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Center for Common Disease Genomics [CCDG] - Neuropsychiatric: SPARK Simons Foundation Powering Autism Research for Knowledge

Project description:Center for Common Disease Genomics [CCDG] - Neuropsychiatric: SPARK Simons Foundation Powering Autism Research for Knowledge

| PRJNA749827 | ENA

Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Simons Searchlight

Project description:Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Simons Searchlight

| PRJNA749821 | ENA

Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Simons Searchlight

Project description:Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Simons Searchlight

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Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Autism - Simons Simplex Collection (SSC)

Project description:Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Autism - Simons Simplex Collection (SSC)

| PRJNA488321 | ENA

Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Autism - Simons Simplex Collection (SSC)

Project description:Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Autism - Simons Simplex Collection (SSC)

| PRJNA488322 | ENA

DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition

Project description:A complex train of events unfolds during brain development, guided by activation/repression of gene expression programs. It remains unclear how this process is disrupted in disease. Here we integrate human genetics with transcriptomic data from differentiation of human embryonic stem cells into cortical excitatory neurons. This reveals a cascade of transcriptional programs activated during early corticoneurogenesis in vitro and in vivo. Genetic variation in these programs is robustly associated with neuropsychiatric disorders and cognitive function, with variants concentrated in loss-of-function intolerant genes. Neurogenic programs also capture schizophrenia GWAS enrichment previously identified in mature excitatory neurons, suggesting that pathways activated during pre-natal development underlie disease-relevant deficits in mature neuronal function. Down-regulation of these programs in DLG2-/- lines delays expression of cell-type identity and impairs neuronal migration, morphology and action potential generation, validating predicted deficits. These data implicate specific cellular pathways underlying neurodevelopment in the aetiology of multiple neuropsychiatric disorders and cognition.

2021-11-11 | PXD029526 | Pride

RNA isoform repertoire of neuropsychiatric risk genes in human brain

Project description:Neuropsychiatric disorders are highly complex conditions and the risk of developing a disorder has been tied to hundreds of genomic variants that alter the expression and/or products (isoforms) made by risk genes. However, how these genes contribute to disease risk and onset through altered expression and RNA splicing is not well understood. Here we show our current understanding of gene isoforms is far from complete and reveal the precise splicing profiles of neuropsychiatric disorder risk genes. Combining our new bioinformatic pipeline IsoLamp with nanopore long-read amplicon sequencing, we deeply profiled the RNA isoform repertoire of 31 high-confidence neuropsychiatric disorder risk genes in human brain. We show most risk genes are more complex than previously reported, identifying 443 novel isoforms and 28 novel exons, including isoforms which alter protein domains, and genes such as ATG13 and GATAD2A where most expression was from previously undiscovered isoforms. The greatest isoform diversity was present in the schizophrenia risk gene ITIH4. Mass spectrometry of brain protein isolates confirmed translation of a novel exon skipping event in ITIH4, suggesting a new regulatory mechanism for this gene in brain. Our results emphasize the widespread presence of previously undetected RNA and protein isoforms in brain and provide an effective approach to address this knowledge gap. Uncovering the isoform repertoire of neuropsychiatric risk genes will underpin future analyses of the functional impact these isoforms have on neuropsychiatric disorders, enabling the translation of genomic findings into a pathophysiological understanding of disease.

| EGAS00001007744 | EGA

Neuropsychiatric and clinical correlates to miRNA expression in the frontal cortex of HIV-infected individuals

Project description:Objective: To elucidate molecular mechanisms of neurocognitive dysfunction in long-term HIV-infected individuals by assessing the microRNA (miR) profile and determining clinical and neurocognitive correlates to miR expression. Design: Analysis of miR profile in frontal cortex of retrospectively-identified autopsy cases of longitudinally-followed subjects with HIV-infection and age/sex-matched controls. HIV-subjects had semi-annual neuropsychiatric and clinical testing, at autopsy, tissue was archived. Methods: MiR repertoires were profiled from frontal cortices. Analysis of variance (ANOVA) and Tukey Honestly Sigificant Difference (HSD) tests with Benjamini-Hochberg correction for multiple comparisons were used to compare expression among the three groups. Pairwise correlations were used to identify neuropsychiatric variable that correlatee with expression of miRs. Results: MiRs were significantly different by HIV-status: miR-103, miR-125a, miR-380, miR-422a, miR-515, miR-520b, miR0618, miR-886, and miR-9. Many miRs correlated with neuropsychiatric outcomes like Learning, Memory, Executive, Verbal, and Motor deficit scores. Conclusions: MiRs are clearly dysregulated in the frontal cortex of HIV-positive individuals. Only a few miRs were significantly dysregulated in only the methamphetamine group. Our study identifies miRs that form rational targets for further inquiry on biochemical mechanisms of HIV-related neurocognitive deficits. Learning deficit score correlates with expression of more miRs than other parameters. A total of 11 HIV positive individuals were analyzed, 5 of which had a past history of methamphetamine ABUSE, and 5 age-matched HIV-negative normal Controls. Technical duplicates are included. Included are clinical and neuropsychiatric data from most recent visit before time of death. This is a retrospective autopsy study of longitudinally-followed subjects on miRNA levels in the frontal cortex.

2013-01-01 | E-GEOD-41952 | biostudies-arrayexpress

DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition

Project description:Brain development requires a complex choreography of cell proliferation, specialisation, migration and network formation, guided by the activation and repression of gene expression programs. It remains unclear how this process is disrupted in neuropsychiatric disorders. Here we integrate human genetics with transcriptomic data from the differentiation of human embryonic stem cells into cortical excitatory neurons. This reveals a cascade of transcriptional programs, activated during early corticoneurogenesis in vitro and in vivo, in which genetic variation is robustly associated with neuropsychiatric disorders and cognitive function. Within these early neurogenic programs, genetic risk is concentrated in loss-of-function intolerant (LoFi) genes, capturing virtually all LoFi disease association. Down-regulation of these programs in DLG2 knockout lines delays expression of cell-type identity alongside marked deficits in neuronal migration, morphology and action potential generation, validating computational predictions. These data implicate specific cellular pathways and neurodevelopmental processes in the aetiology of multiple neuropsychiatric disorders and cognition.

2021-10-30 | GSE172199 | GEO

Accelerated knowledge discovery from omics data by optimal experimental design

Project description:Accelerated knowledge discovery from omics data by optimal experimental design

| PRJNA604190 | ENA