New considerations for hiPSC-based models of neuropsychiatric disorders

Abstract

The development of human-induced pluripotent stem cells (hiPSCs) has made possible patient-specific modeling across the spectrum of human disease. Here, we discuss recent advances in psychiatric genomics and post-mortem studies that provide critical insights concerning cell-type composition and sample size that should be considered when designing hiPSC-based studies of complex genetic disease. We review recent hiPSC-based models of SZ, in light of our new understanding of critical power limitations in the design of hiPSC-based studies of complex genetic disorders. Three possible solutions are a movement towards genetically stratified cohorts of rare variant patients, application of CRISPR technologies to engineer isogenic neural cells to study the impact of common variants, and integration of advanced genetics and hiPSC-based datasets in future studies. Overall, we emphasize that to advance the reproducibility and relevance of hiPSC-based studies, stem cell biologists must contemplate statistical and biological considerations that are already well accepted in the field of genetics. We conclude with a discussion of the hypothesis of biological convergence of disease—through molecular, cellular, circuit, and patient level phenotypes—and how this might emerge through hiPSC-based studies.

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Acknowledgements

Kristen J. Brennand is a New York Stem Cell Foundation—Robertson Investigator. The Brennand Laboratory is supported by a Brain and Behavior Young Investigator Grant, National Institute of Health (NIH) grants R01MH101454 and R01MH106056 and the New York Stem Cell Foundation. Erin Flaherty is supported by F31MH112285. Gabriel E. Hoffman is partially supported by a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation.

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Hoffman, G.E., Schrode, N., Flaherty, E. et al. New considerations for hiPSC-based models of neuropsychiatric disorders. Mol Psychiatry 24, 49–66 (2019). https://doi.org/10.1038/s41380-018-0029-1

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