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Modeling the complex genetic architectures of brain disease

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.

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Fig. 1: 2D versus 3D culture systems to resolve cell-type effects and interactions.
Fig. 2: Unidirectional and bidirectional network perturbations.
Fig. 3: Coupling hiPSC and CRISPR platforms to accelerate functional validations of brain disease-risk loci.

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Acknowledgements

This work was partially supported by US National Institutes of Health (NIH) grants R56 MH101454 (K.J.B.), R01 MH106056 (K.J.B.) and R01 MH109897 (K.J.B.).

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M.B.F., T.A. and K.J.B. wrote the manuscript.

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Correspondence to Kristen J. Brennand.

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Fernando, M.B., Ahfeldt, T. & Brennand, K.J. Modeling the complex genetic architectures of brain disease. Nat Genet 52, 363–369 (2020). https://doi.org/10.1038/s41588-020-0596-3

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