Publications by authors named "S D Detera-Wadleigh"
Article Synopsis
- Schizophrenia is a complex psychiatric disorder influenced by multiple genetic factors, and recent studies suggest that these genetic variations affect common molecular mechanisms within the brain.
- By using induced pluripotent stem cells from individuals with varying genetic risks, researchers found significant differences in alternative polyadenylation (APA) of synaptic genes, which correlated with reduced synaptic density.
- The study identified the RNA binding protein PTBP2 as a key factor influencing these changes in gene expression, highlighting a potential molecular pathway that connects genetic risk to synaptic dysfunction in schizophrenia.
Genome-wide (GWAS) and copy number variant (CNV) association studies have reproducibly identified numerous risk alleles associated with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ), but biological characterization of these alleles lags gene discovery, owing to the inaccessibility of live human brain cells and inadequate animal models for human psychiatric conditions. Human-derived induced pluripotent stem cells (iPSCs) provide a renewable cellular reagent that can be differentiated into living, disease-relevant cells and 3D brain organoids carrying the full complement of genetic variants present in the donor germline. Experimental studies of iPSC-derived cells allow functional characterization of risk alleles, establishment of causal relationships between genes and neurobiology, and screening for novel therapeutics.
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- - The study examines gene expression differences in the subgenual anterior cingulate cortex (sgACC) among individuals with bipolar disorder, schizophrenia, major depression, and healthy controls, using RNA from 200 postmortem donors.
- - Researchers found that while there were modest expression differences across disorders, case-case comparisons showed greater variations, with some gene transcripts displaying opposing expression patterns between diagnostic groups.
- - The study highlights that certain rare gene transcripts linked to synapse formation and cell junctions are differentially expressed and suggests that common genetic variants associated with mental illness risk may influence these gene expressions, impacting our understanding of psychiatric diagnoses.
Biological characterization of genetic variants identified in genome-wide association studies (GWAS) remains a substantial challenge. Here we used human-induced pluripotent stem cells (iPSC) and their neural derivatives to characterize common variants on chromosome 3p22 that have been associated by GWAS with major mental illnesses. IPSC-derived neural progenitor cells carrying the risk allele of the single nucleotide polymorphism (SNP), rs9834970, displayed lower baseline TRANK1 expression that was rescued by chronic treatment with therapeutic dosages of valproic acid (VPA).
View Article and Find Full Text PDFWe sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels.
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