Prefrontal Coexpression of Schizophrenia Risk Genes Is Associated With Treatment Response in Patients.
Adolescent
Adult
Aged
Aged, 80 and over
Antipsychotic Agents
/ therapeutic use
Computational Biology
Female
Gene Expression
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Olanzapine
/ therapeutic use
Prefrontal Cortex
/ drug effects
Schizophrenia
/ drug therapy
Transcriptome
Treatment Outcome
Young Adult
Dorsolateral prefrontal cortex
Gene coexpression networks
Olanzapine
RNA sequencing
Schizophrenia
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 07 2019
01 07 2019
Historique:
received:
27
06
2018
revised:
13
03
2019
accepted:
14
03
2019
pubmed:
28
5
2019
medline:
11
6
2020
entrez:
26
5
2019
Statut:
ppublish
Résumé
Gene coexpression networks are relevant to functional and clinical translation of schizophrenia risk genes. We hypothesized that schizophrenia risk genes converge into coexpression pathways that may be associated with gene regulation mechanisms and with response to treatment in patients with schizophrenia. We identified gene coexpression networks in two prefrontal cortex postmortem RNA sequencing datasets (n = 688) and replicated them in four more datasets (n = 1295). We identified and replicated (p values < .001) a single module enriched for schizophrenia risk loci (13 risk genes in 10 loci). In silico screening of potential regulators of the schizophrenia risk module via bioinformatic analyses identified two transcription factors and three microRNAs associated with the risk module. To translate postmortem information into clinical phenotypes, we identified polymorphisms predicting coexpression and combined them to obtain an index approximating module coexpression (Polygenic Coexpression Index [PCI]). The PCI-coexpression association was successfully replicated in two independent brain transcriptome datasets (n = 131; p values < .05). Finally, we tested the association between the PCI and short-term treatment response in two independent samples of patients with schizophrenia treated with olanzapine (n = 167). The PCI was associated with treatment response in the positive symptom domain in both clinical cohorts (p values < .05). In summary, our findings in 1983 samples of human postmortem prefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. This coexpression pathway may be coregulated by transcription factors and microRNA associated with it.
Sections du résumé
BACKGROUND
Gene coexpression networks are relevant to functional and clinical translation of schizophrenia risk genes. We hypothesized that schizophrenia risk genes converge into coexpression pathways that may be associated with gene regulation mechanisms and with response to treatment in patients with schizophrenia.
METHODS
We identified gene coexpression networks in two prefrontal cortex postmortem RNA sequencing datasets (n = 688) and replicated them in four more datasets (n = 1295). We identified and replicated (p values < .001) a single module enriched for schizophrenia risk loci (13 risk genes in 10 loci). In silico screening of potential regulators of the schizophrenia risk module via bioinformatic analyses identified two transcription factors and three microRNAs associated with the risk module. To translate postmortem information into clinical phenotypes, we identified polymorphisms predicting coexpression and combined them to obtain an index approximating module coexpression (Polygenic Coexpression Index [PCI]).
RESULTS
The PCI-coexpression association was successfully replicated in two independent brain transcriptome datasets (n = 131; p values < .05). Finally, we tested the association between the PCI and short-term treatment response in two independent samples of patients with schizophrenia treated with olanzapine (n = 167). The PCI was associated with treatment response in the positive symptom domain in both clinical cohorts (p values < .05).
CONCLUSIONS
In summary, our findings in 1983 samples of human postmortem prefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. This coexpression pathway may be coregulated by transcription factors and microRNA associated with it.
Identifiants
pubmed: 31126695
pii: S0006-3223(19)31152-7
doi: 10.1016/j.biopsych.2019.03.981
pii:
doi:
Substances chimiques
Antipsychotic Agents
0
Olanzapine
N7U69T4SZR
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
45-55Informations de copyright
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.