Modeling the complex genetic architectures of brain disease
- 22 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 52 (4), 363-369
- https://doi.org/10.1038/s41588-020-0596-3
Abstract
The genetic architecture of each individual comprises common and rare variants that, acting alone and in combination, confer risk of disease. The cell-type-specific and/or context-dependent functional consequences of the risk variants linked to brain disease must be resolved. Coupling human induced pluripotent stem cell (hiPSC)-based technology with CRISPR-based genome engineering facilitates precise isogenic comparisons of variants across genetic backgrounds. Although functional-validation studies are typically performed on one variant in isolation and in one cell type at a time, complex genetic diseases require multiplexed gene perturbations to interrogate combinations of genes and resolve physiologically relevant disease biology. Our aim is to discuss advances at the intersection of genomics, hiPSCs and CRISPR. A better understanding of the molecular mechanisms underlying disease risk will improve genetic diagnosis, drive phenotypic drug discovery and pave the way toward precision medicine. Combining genomic data with CRISPR, hiPSC and organoid technologies provides platforms to study the complex genetic architectures of brain disease. These studies could improve genetic diagnosis, drive drug discovery and move the field toward precision medicine.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R56MH101454)
This publication has 91 references indexed in Scilit:
- Genome engineering using the CRISPR-Cas9 systemNature Protocols, 2013
- CRISPR-Mediated Modular RNA-Guided Regulation of Transcription in EukaryotesCell, 2013
- Rapid Single-Step Induction of Functional Neurons from Human Pluripotent Stem CellsNeuron, 2013
- Rapid Generation of Functional Dopaminergic Neurons From Human Induced Pluripotent Stem Cells Through a Single-Step Procedure Using Cell Lineage Transcription FactorsStem Cells Translational Medicine, 2013
- Functional Maturation of hPSC-Derived Forebrain Interneurons Requires an Extended Timeline and Mimics Human Neural DevelopmentCell Stem Cell, 2013
- Repurposing CRISPR as an RNA-Guided Platform for Sequence-Specific Control of Gene ExpressionCell, 2013
- Multiplex Genome Engineering Using CRISPR/Cas SystemsScience, 2013
- Modeling human cortical development in vitro using induced pluripotent stem cellsProceedings of the National Academy of Sciences of the United States of America, 2012
- Modelling schizophrenia using human induced pluripotent stem cellsNature, 2011
- The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNANature, 2010