Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms

Publication date: 17 October 2019Source: Cell, Volume 179, Issue 3Author(s): Rebecca L. Walker, Gokul Ramaswami, Christopher Hartl, Nicholas Mancuso, Michael J. Gandal, Luis de la Torre-Ubieta, Bogdan Pasaniuc, Jason L. Stein, Daniel H. GeschwindSummaryTissue-specific regulatory regions harbor substantial genetic risk for disease. Because brain development is a critical epoch for neuropsychiatric disease susceptibility, we characterized the genetic control of the transcriptome in 201 mid-gestational human brains, identifying 7,962 expression quantitative trait loci (eQTL) and 4,635 spliceQTL (sQTL), including several thousand prenatal-specific regulatory regions. We show that significant genetic liability for neuropsychiatric disease lies within prenatal eQTL and sQTL. Integration of eQTL and sQTL with genome-wide association studies (GWAS) via transcriptome-wide association identified dozens of novel candidate risk genes, highlighting shared and stage-specific mechanisms in schizophrenia (SCZ). Gene network analysis revealed that SCZ and autism spectrum disorder (ASD) affect distinct developmental gene co-expression modules. Yet, in each disorder, common and rare genetic variation converges within modules, which in ASD implicates superficial cortical neurons. More broadly, these data, available as a web browser and our analyses, demonstrate the genetic mechanisms by which developmental events have a widespread influence on adult anatomical and behavioral phenotypes.Graphical...
Source: Cell - Category: Cytology Source Type: research

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We report here the derivation of familial iPSC lines from two controls and three ASD patients carrying NRXN1α+/−, using a non-integrating Sendai viral kit. The genotype and karyotype of the resulting iPSCs were validated by whole genome SNP array. All iPSC lines expressed comparable levels of pluripotency markers and could be differentiated into three germ layers.
Source: Stem Cell Research - Category: Stem Cells Source Type: research
Publication date: Available online 13 November 2019Source: NeuroImage: ClinicalAuthor(s): Liron Rabany, Sophy Brocke, Vince D. Calhoun, Brian Pittman, Silvia Corbera, Bruce E. Wexler, Morris D. Bell, Kevin Pelphrey, Godfrey D. Pearlson, Michal Assaf
Source: NeuroImage: Clinical - Category: Radiology Source Type: research
Molecular Psychiatry, Published online: 08 November 2019; doi:10.1038/s41380-019-0576-0Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations
Source: Molecular Psychiatry - Category: Psychiatry Authors: Source Type: research
Abstract The complement cascade is an important arm of the immune system that plays a key role in protecting the central nervous system (CNS) from infection. Recently, it has also become clear that complement proteins have fundamental roles in the developing and aging CNS that are distinct from their roles in immunity. During neurodevelopment, complement signalling is involved in diverse processes including neural tube closure, neural progenitor proliferation and differentiation, neuronal migration, and synaptic pruning. In acute neurotrauma and ischamic brain injury, complement drives inflammation and neuronal de...
Source: Seminars in Immunology - Category: Allergy & Immunology Authors: Tags: Semin Immunol Source Type: research
Abstract The laminar structure, a unique feature of the mammalian cerebrum, is formed by a number of genes in a highly complex process. The pyramidal neurons that make up each layer of the cerebrum are functionally characterized by specific gene expressions. In particular, Cux1 and Cux2, which are specifically expressed in layer II-IV neurons, are known to regulate dendritic branching, spine morphology, and synapse formation. However, it is still unknown how their expression is regulated transcriptionally. Here we constructed Cux2-mCherry transgenic mice that reproduce the cortical layer II-IV-specific expression ...
Source: Biochemical and Biophysical Research communications - Category: Biochemistry Authors: Tags: Biochem Biophys Res Commun Source Type: research
Abstract The CYFIP1 gene has been linked to autism and schizophrenia and, while there is a noted heterogeneity, both have been characterized to be disorders of connectivity. Recent studies by Dominquez-Iturza et al. and Silva et al. provide direct evidence for CYFIP1 in functional and structural connectivity in the brain. PMID: 31704178 [PubMed - as supplied by publisher]
Source: Trends in Neurosciences - Category: Neuroscience Authors: Tags: Trends Neurosci Source Type: research
This study characterized social play by proteomic and transcriptional profiling studies. Social play was performed on male Sprague Dawley rats on postnatal day 38 and protein and gene expression in the amygdala was determined following behavioral testing. The proteomic analysis led to the identification of 170 differentially expressed proteins (p ≤0.05) with 67 upregulated and 103 downregulated proteins. The transcriptomic analysis led to the identification of 188 genes (adjusted p≤0.05) with 55 upregulated and 133 downregulated genes. Based on both protein and gene expression data, DAVID analysis revealed that socia...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Rattus norvegicus Source Type: research
Publication date: Available online 1 November 2019Source: Progress in Neuro-Psychopharmacology and Biological PsychiatryAuthor(s): Débora Dreher Nabinger, Stefani Altenhofen, Carla Denise BonanAbstractZebrafish (Danio rerio) has been considered a complementary model for biomedical studies, especially due to advantages such as external and rapid development, and genetic manipulation. There is growing interest in this model in neuroscience research since the species has morphological and physiological similarities to mammals and a complex behavioral repertoire. The purinergic signaling has been described in zebrafish,...
Source: Progress in Neuro Psychopharmacology and Biological Psychiatry - Category: Psychiatry Source Type: research
Publication date: Available online 31 October 2019Source: Schizophrenia Research: CognitionAuthor(s): Margherita Bechi, Giulia Agostoni, Mariachiara Buonocore, Davide Gritti, Mattia Mascia, Marco Spangaro, Laura Bianchi, Federica Cocchi, Carmelo Guglielmino, Marta Bosia, Roberto CavallaroAbstractLiterature has recently identified a discrete subgroup of patients affected by schizophrenia that also present autistic traits (ATs), showing a peculiar cognitive, clinical and functional profile. Theory of Mind (ToM) represents a core, impaired feature in both schizophrenia and Autism Spectrum Disorder (ASD), ToM in patients with ...
Source: Schizophrenia Research: Cognition - Category: Psychiatry Source Type: research
Publication date: Available online 30 October 2019Source: Progress in Neuro-Psychopharmacology and Biological PsychiatryAuthor(s): Talitha C. Ford, Will Woods, Peter G. Enticott, David P. CrewtherAbstractSeveral lines of evidence identify aberrant excitatory-inhibitory neural processes across autism and schizophrenia spectrum disorders, particularly within the psychosocial domain. Such neural processes include increased excitatory glutamate and reduced inhibitory GABA concentrations, which may affect auditory pre-attentive processing as indexed by the mismatch negativity (MMN); thus, an excitation-inhibition imbalance migh...
Source: Progress in Neuro Psychopharmacology and Biological Psychiatry - Category: Psychiatry Source Type: research
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