Publication

A longitudinal model of human neuronal differentiation for functional investigation of schizophrenia polygenic risk

Ori, A. P. S., Bot, M. H. M., Molenhuis, R. T., Olde Loohuis, L. M. & Ophoff, R. A., 1-Apr-2019, In : Biological Psychiatry. 85, 7, p. 544-553 10 p.

Research output: Contribution to journalArticleAcademicpeer-review

Background Common psychiatric disorders are characterized by complex disease architectures with many small genetic effects that contribute and complicate biological understanding of their etiology. There is therefore a pressing need for in vitro experimental systems that allow for interrogation of polygenic psychiatric disease risk to study the underlying biological mechanisms. Methods We have developed an analytical framework that integrates genome-wide disease risk from genome-wide association studies with longitudinal in vitro gene expression profiles of human neuronal differentiation. Results We demonstrate that the cumulative impact of risk loci of specific psychiatric disorders is significantly associated with genes that are differentially expressed and upregulated during differentiation. We find the strongest evidence for schizophrenia, a finding that we replicate in an independent dataset. A longitudinal gene cluster involved in synaptic function primarily drives the association with schizophrenia risk. Conclusions These findings reveal that in vitro human neuronal differentiation can be used to translate the polygenic architecture of schizophrenia to biologically relevant pathways that can be modeled in an experimental system. Overall, this work emphasizes the use of longitudinal in vitro transcriptomic signatures as a cellular readout and the application to the genetics of complex traits.
Original languageEnglish
Pages (from-to)544-553
Number of pages10
JournalBiological Psychiatry
Volume85
Issue number7
Early online date6-Sep-2018
Publication statusPublished - 1-Apr-2019
Externally publishedYes

    Keywords

  • Genome-wide disease risk, Neuronal stem cells, Polygenicity, Psychiatric disorders, Schizophrenia, Synaptic function

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