A Longitudinal Model of Human Neuronal Differentiation for Functional Investigation of Schizophrenia Polygenic Risk.
Biol Psychiatry
; 85(7): 544-553, 2019 04 01.
Article
em En
| MEDLINE
| ID: mdl-30340753
ABSTRACT
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esquizofrenia
/
Diferenciação Celular
/
Predisposição Genética para Doença
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Herança Multifatorial
/
Perfilação da Expressão Gênica
/
Estudo de Associação Genômica Ampla
/
Células-Tronco Neurais
/
Modelos Neurológicos
Tipo de estudo:
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article