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Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report

The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diag...

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Autores principales: Breen, M S, Uhlmann, A, Nday, C M, Glatt, S J, Mitt, M, Metsalpu, A, Stein, D J, Illing, N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070070/
https://www.ncbi.nlm.nih.gov/pubmed/27163203
http://dx.doi.org/10.1038/tp.2016.67
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author Breen, M S
Uhlmann, A
Nday, C M
Glatt, S J
Mitt, M
Metsalpu, A
Stein, D J
Illing, N
author_facet Breen, M S
Uhlmann, A
Nday, C M
Glatt, S J
Mitt, M
Metsalpu, A
Stein, D J
Illing, N
author_sort Breen, M S
collection PubMed
description The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diagnosing MAP accurately at the molecular and neurocognitive level before the MAP model can contribute to the discovery of SCZ biomarkers. We directly assessed subcortical brain structural volumes and clinical parameters of MAP within the framework of an integrative genome-wide RNA-Seq blood transcriptome analysis of subjects diagnosed with MAP (N=10), METH dependency without psychosis (MA; N=10) and healthy controls (N=10). First, we identified discrete groups of co-expressed genes (that is, modules) and tested them for functional annotation and phenotypic relationships to brain structure volumes, life events and psychometric measurements. We discovered one MAP-associated module involved in ubiquitin-mediated proteolysis downregulation, enriched with 61 genes previously found implicated in psychosis and SCZ across independent blood and post-mortem brain studies using convergent functional genomic (CFG) evidence. This module demonstrated significant relationships with brain structure volumes including the anterior corpus callosum (CC) and the nucleus accumbens. Furthermore, a second MAP and psychoticism-associated module involved in circadian clock upregulation was also enriched with 39 CFG genes, further associated with the CC. Subsequently, a machine-learning analysis of differentially expressed genes identified single blood-based biomarkers able to differentiate controls from methamphetamine dependents with 87% accuracy and MAP from MA subjects with 95% accuracy. CFG evidence validated a significant proportion of these putative MAP biomarkers in independent studies including CLN3, FBP1, TBC1D2 and ZNF821 (RNA degradation), ELK3 and SINA3 (circadian clock) and PIGF and UHMK1 (ubiquitin-mediated proteolysis). Finally, focusing analysis on brain structure volumes revealed significantly lower bilateral hippocampal volumes in MAP subjects. Overall, these results suggest similar molecular and neurocognitive mechanisms underlying the pathophysiology of psychosis and SCZ regardless of substance abuse and provide preliminary evidence supporting the MAP paradigm as an exemplar for SCZ biomarker discovery.
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spelling pubmed-50700702016-10-19 Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report Breen, M S Uhlmann, A Nday, C M Glatt, S J Mitt, M Metsalpu, A Stein, D J Illing, N Transl Psychiatry Original Article The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diagnosing MAP accurately at the molecular and neurocognitive level before the MAP model can contribute to the discovery of SCZ biomarkers. We directly assessed subcortical brain structural volumes and clinical parameters of MAP within the framework of an integrative genome-wide RNA-Seq blood transcriptome analysis of subjects diagnosed with MAP (N=10), METH dependency without psychosis (MA; N=10) and healthy controls (N=10). First, we identified discrete groups of co-expressed genes (that is, modules) and tested them for functional annotation and phenotypic relationships to brain structure volumes, life events and psychometric measurements. We discovered one MAP-associated module involved in ubiquitin-mediated proteolysis downregulation, enriched with 61 genes previously found implicated in psychosis and SCZ across independent blood and post-mortem brain studies using convergent functional genomic (CFG) evidence. This module demonstrated significant relationships with brain structure volumes including the anterior corpus callosum (CC) and the nucleus accumbens. Furthermore, a second MAP and psychoticism-associated module involved in circadian clock upregulation was also enriched with 39 CFG genes, further associated with the CC. Subsequently, a machine-learning analysis of differentially expressed genes identified single blood-based biomarkers able to differentiate controls from methamphetamine dependents with 87% accuracy and MAP from MA subjects with 95% accuracy. CFG evidence validated a significant proportion of these putative MAP biomarkers in independent studies including CLN3, FBP1, TBC1D2 and ZNF821 (RNA degradation), ELK3 and SINA3 (circadian clock) and PIGF and UHMK1 (ubiquitin-mediated proteolysis). Finally, focusing analysis on brain structure volumes revealed significantly lower bilateral hippocampal volumes in MAP subjects. Overall, these results suggest similar molecular and neurocognitive mechanisms underlying the pathophysiology of psychosis and SCZ regardless of substance abuse and provide preliminary evidence supporting the MAP paradigm as an exemplar for SCZ biomarker discovery. Nature Publishing Group 2016-05 2016-05-10 /pmc/articles/PMC5070070/ /pubmed/27163203 http://dx.doi.org/10.1038/tp.2016.67 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Breen, M S
Uhlmann, A
Nday, C M
Glatt, S J
Mitt, M
Metsalpu, A
Stein, D J
Illing, N
Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report
title Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report
title_full Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report
title_fullStr Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report
title_full_unstemmed Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report
title_short Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report
title_sort candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative rna-sequencing report
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070070/
https://www.ncbi.nlm.nih.gov/pubmed/27163203
http://dx.doi.org/10.1038/tp.2016.67
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