Mapping cis-regulatory elements in human excitatory and inhibitory neurons links psychiatric disease heritability and activity-regulated transcriptional programs
Ontology highlight
ABSTRACT: Genome-wide association studies (GWAS) have identified hundreds of loci associated with psychiatric diseases, yet there is a lack of understanding of disease pathophysiology. Common risk variants can shed light on the molecular mechanisms underlying these diseases; however, identifying specific causal variants remains challenging. An added complication is that most common risk variants are in non-coding regions. Their impact is likely to be restricted to particular cell types, developmental stages, or cell states. Here, we comprehensively mapped cis-regulatory elements in two defined populations of human excitatory and inhibitory neurons derived from pluripotent stem cells.
Project description:Genome-wide association studies (GWAS) have identified hundreds of loci associated with psychiatric diseases, yet there is a lack of understanding of disease pathophysiology. Common risk variants can shed light on the molecular mechanisms underlying these diseases; however, identifying specific causal variants remains challenging. An added complication is that most common risk variants are in non-coding regions. Their impact is likely to be restricted to particular cell types, developmental stages, or cell states. Here, we comprehensively mapped cis-regulatory elements in two defined populations of human excitatory and inhibitory neurons derived from pluripotent stem cells.
Project description:Genome-wide association studies (GWAS) have identified hundreds of loci associated with psychiatric diseases, yet there is a lack of understanding of disease pathophysiology. Common risk variants can shed light on the molecular mechanisms underlying these diseases; however, identifying specific causal variants remains challenging. An added complication is that most common risk variants are in non-coding regions. Their impact is likely to be restricted to particular cell types, developmental stages, or cell states. Here, we comprehensively mapped cis-regulatory elements in two defined populations of human excitatory and inhibitory neurons derived from pluripotent stem cells.
Project description:In psychiatric disorders, common and rare genetic variants cause widespread dysfunction of cells and their interactions, especially in the prefrontal cortex, giving rise to psychiatric symptoms. To better understand these processes, we traced the effects of common and rare genetics, and cumulative disease risk scores, to their molecular footprints in human cortical single-cell types. We demonstrated that examining gene expression at single-exon resolution is crucial for understanding the cortical dysregulation associated with diagnosis and genetic risk derived from common variants. We then used disease risk scores to identify a core set of genes that serve as a footprint of common and rare variants in the cortex. Pathways enriched in these genes included dopamine regulation, circadian entrainment, and hormone regulation. Single-nuclei-RNA-sequencing pinpointed these enriched genes to excitatory cortical neurons. This study highlights the importance of studying sub-gene-level genetic architecture to classify psychiatric disorders based on biology rather than symptomatology, to identify novel targets for treatment development.
Project description:Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mech- anisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic dif- ferences in GR-induced transcriptional activation may mediate the risk for depression and other psy- chiatric disorders by altering a network of function- ally related stress-sensitive genes in blood and brain.
Project description:Recent genetic studies have found common genomic risk variants among psychiatric disorders, strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis using genome-edited iPSC cells with the loss of function variants on both alleles revealed that the expression level of ZNF558, a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2-deleted neuronal cells.
Project description:Our study aims to lay the basis for a predictive modeling service for postoperative complications and prolonged hospital stay in patients suffering from psychiatric diseases undergoing colorectal surgery.
Furthermore, we aim to investigate the impact of preoperative Risk factors, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and the complications after colorectal surgeries like anastomosis insufficiency via predictive modeling techniques
The service mentioned above will be publicly available as a web-based application
Project description:MicroRNAs have been implicated in the pathology not only of cancer, but also of psychiatric diseases, such as bipolar disorder and schizophrenia. As several psychiatric disorders share the same risk genes, we hypothesized that this microRNA could also be associated with attention-deficit/hyperactivity disorder (ADHD) and that this association to psychiatric disorders might be due to the variable number of tandem repeats (VNTR) polymorphism within the internal miR-137 (Imir137) promoter (PMID 18316599; PMID 25154622). To further understand the role of the microRNA 137 in the brain a knock-down of miR-137 expression in SH-SY5Y neuroblastoma cells was performed followed by expression analysis using a microarray.
Project description:Mapping cis-regulatory elements in human excitatory and inhibitory neurons links psychiatric disease heritability and activity-regulated transcriptional programs
Project description:Mapping cis-regulatory elements in human excitatory and inhibitory neurons links psychiatric disease heritability and activity-regulated transcriptional programs