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Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide

Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the patho...

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Autores principales: Murphy, T M, Crawford, B, Dempster, E L, Hannon, E, Burrage, J, Turecki, G, Kaminsky, Z, Mill, J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545719/
https://www.ncbi.nlm.nih.gov/pubmed/28045465
http://dx.doi.org/10.1038/tp.2016.249
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author Murphy, T M
Crawford, B
Dempster, E L
Hannon, E
Burrage, J
Turecki, G
Kaminsky, Z
Mill, J
author_facet Murphy, T M
Crawford, B
Dempster, E L
Hannon, E
Burrage, J
Turecki, G
Kaminsky, Z
Mill, J
author_sort Murphy, T M
collection PubMed
description Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.
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spelling pubmed-55457192017-08-07 Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide Murphy, T M Crawford, B Dempster, E L Hannon, E Burrage, J Turecki, G Kaminsky, Z Mill, J Transl Psychiatry Original Article Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers. Nature Publishing Group 2017-01 2017-01-03 /pmc/articles/PMC5545719/ /pubmed/28045465 http://dx.doi.org/10.1038/tp.2016.249 Text en Copyright © 2017 The Author(s) 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
Murphy, T M
Crawford, B
Dempster, E L
Hannon, E
Burrage, J
Turecki, G
Kaminsky, Z
Mill, J
Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide
title Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide
title_full Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide
title_fullStr Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide
title_full_unstemmed Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide
title_short Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide
title_sort methylomic profiling of cortex samples from completed suicide cases implicates a role for psors1c3 in major depression and suicide
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545719/
https://www.ncbi.nlm.nih.gov/pubmed/28045465
http://dx.doi.org/10.1038/tp.2016.249
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