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      Methylomic changes during conversion to psychosis

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          Abstract

          The onset of psychosis is the consequence of complex interactions between genetic vulnerability to psychosis and response to environmental and/or maturational changes. Epigenetics is hypothesized to mediate the interplay between genes and environment leading to the onset of psychosis. We believe we performed the first longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals referred to a specialized outpatient unit for early detection of psychosis and enrolled in a 1-year follow-up. We used Infinium HumanMethylation450 BeadChip array after bisulfite conversion and analyzed longitudinal variations in methylation at 411 947 cytosine–phosphate–guanine (CpG) sites. Conversion to psychosis was associated with specific methylation changes. Changes in DNA methylation were significantly different between converters and non-converters in two regions: one located in 1q21.1 and a cluster of six CpG located in GSTM5 gene promoter. Methylation data were confirmed by pyrosequencing in the same population. The 100 top CpGs associated with conversion to psychosis were subjected to exploratory analyses regarding the related gene networks and their capacity to distinguish between converters and non-converters. Cluster analysis showed that the top CpG sites correctly distinguished between converters and non-converters. In this first study of methylation during conversion to psychosis, we found that alterations preferentially occurred in gene promoters and pathways relevant for psychosis, including oxidative stress regulation, axon guidance and inflammatory pathways. Although independent replications are warranted to reach definitive conclusions, these results already support that longitudinal variations in DNA methylation may reflect the biological mechanisms that precipitate some prodromal individuals into full-blown psychosis, under the influence of environmental factors and maturational processes at adolescence.

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          DNA methylation analysis by pyrosequencing.

          Jörg Tost, Ivo Gut (2007)
          Pyrosequencing is a sequencing-by-synthesis method that quantitatively monitors the real-time incorporation of nucleotides through the enzymatic conversion of released pyrophosphate into a proportional light signal. Quantitative measures are of special importance for DNA methylation analysis in various developmental and pathological situations. Analysis of DNA methylation patterns by pyrosequencing combines a simple reaction protocol with reproducible and accurate measures of the degree of methylation at several CpGs in close proximity with high quantitative resolution. After bisulfite treatment and PCR, the degree of each methylation at each CpG position in a sequence is determined from the ratio of T and C. The process of purification and sequencing can be repeated for the same template to analyze other CpGs in the same amplification product. Quantitative epigenotypes are obtained using this protocol in approximately 4 h for up to 96 DNA samples when bisulfite-treated DNA is already available as the starting material.
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            Population analysis of large copy number variants and hotspots of human genetic disease.

            Andy Itsara, Gregory M. Cooper, Carl Baker … (2009)
            Copy number variants (CNVs) contribute to human genetic and phenotypic diversity. However, the distribution of larger CNVs in the general population remains largely unexplored. We identify large variants in approximately 2500 individuals by using Illumina SNP data, with an emphasis on "hotspots" prone to recurrent mutations. We find variants larger than 500 kb in 5%-10% of individuals and variants greater than 1 Mb in 1%-2%. In contrast to previous studies, we find limited evidence for stratification of CNVs in geographically distinct human populations. Importantly, our sample size permits a robust distinction between truly rare and polymorphic but low-frequency copy number variation. We find that a significant fraction of individual CNVs larger than 100 kb are rare and that both gene density and size are strongly anticorrelated with allele frequency. Thus, although large CNVs commonly exist in normal individuals, which suggests that size alone can not be used as a predictor of pathogenicity, such variation is generally deleterious. Considering these observations, we combine our data with published CNVs from more than 12,000 individuals contrasting control and neurological disease collections. This analysis identifies known disease loci and highlights additional CNVs (e.g., 3q29, 16p12, and 15q25.2) for further investigation. This study provides one of the first analyses of large, rare (0.1%-1%) CNVs in the general population, with insights relevant to future analyses of genetic disease.
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              Mapping the onset of psychosis: the Comprehensive Assessment of At-Risk Mental States.

              Alison R Yung, Hok Pan Yuen, Patrick D McGorry … (2015)
              Recognizing the prodrome of a first psychotic episode prospectively creates the opportunity of intervention, which could delay, ameliorate or even prevent onset. Valid criteria and a reliable methodology for identifying possible prodromes are needed. This paper describes an instrument, the Comprehensive Assessment of At-Risk Mental States (CAARMS), which has been designed for such a purpose. It has two functions: (i) to assess psychopathology thought to indicate imminent development of a first-episode psychotic disorder; and (ii) to determine if an individual meets criteria for being at ultra high risk (UHR) for onset of first psychotic disorder. This paper describes the pilot evaluation of the CAARMS. Several methodologies were used to test the CAARMS. First, CAARMS scores in a group of UHR young people and the association between CAARMS scores and the risk of transition to psychotic disorder, were analysed. Second, CAARMS scores in a UHR group were compared to a control group. To assess concurrent validity, CAARMS-defined UHR criteria were compared to the existing criteria for identifying the UHR cohort. To assess predictive validity, the CAARMS-defined UHR criteria were applied to a sample of 150 non-psychotic help-seekers and rates of onset of psychotic disorder at 6-month follow-up determined for the CAARMS-positive (i.e. met UHR criteria) group and the CAARMS-negative (i.e. did not meet UHR criteria) group. The inter-rater reliability of the CAARMS was assessed by using pairs of raters. High CAARMS score in the UHR group was significantly associated with onset of psychotic disorder. The control group had significantly lower CAARMS scores than the UHR group. The UHR criteria assessed by the CAARMS identified a similar group to the criteria measured by existing methodology. In the sample of non-psychotic help-seekers those who were CAARMS-positive were at significantly increased risk of onset of psychotic disorder compared to those who were CAARMS-negative (relative risk of 12.44 (95% CI = 1.5-103.41, p = 0.0025)). The CAARMS had good to excellent reliability. In these preliminary investigations, the CAARMS displayed good to excellent concurrent, discriminant and predictive validity and excellent inter-rater reliability. The CAARMS instrument provides a useful platform for monitoring subthreshold psychotic symptoms for worsening into full-threshold psychotic disorder.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Psychiatry
                Journal ID (iso-abbrev): Mol. Psychiatry
                Title: Molecular Psychiatry
                Publisher: Nature Publishing Group
                ISSN (Print): 1359-4184
                ISSN (Electronic): 1476-5578
                Publication date (Print): April 2017
                Publication date (Electronic): 26 April 2016
                Volume: 22
                Issue: 4
                Pages: 512-518
                Affiliations
                [1 ]Université Paris Descartes, PRES Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894 , Paris, France
                [2 ]INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S 894 , Paris, France
                [3 ]CNRS, GDR3557-Institut de Psychiatrie , Paris, France
                [4 ]Faculté de Médecine Paris Descartes, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire , Paris, France
                [5 ]CNRS, UMR7216 Épigénétique et Destin Cellulaire , Paris, France
                [6 ]Université Paris Diderot, Sorbonne Paris Cité , Paris, France
                [7 ]Département Hospitalo-Universitaire DHU PROTECT , Paris, France
                [8 ]Université de Montréal, Beaulieu-Saucier Pharmacogenomics Center, Montréal Heart Institute , Montréal, QC, Canada
                Author notes
                [* ]Laboratoire de Physiopathologie de Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, Service Hospitalo-Universitaire, INSERM U894—Université Paris Descartes , 2 ter rue d'Alesia, Paris 75014, France. E-mail: marie-odile.krebs@ 123456inserm.fr
                [9]

                These authors contributed equally to this work.

                [*]

                Members of the ICAAR team Célia Mam-Lam-Fook, Charlotte Alexandre, Emilie Magaud, Gilles Martinez, Mathilde Kazes, Mélanie Chayet, Olivier Gay, Zelda Prost.

                Article
                Publisher Item ID: mp201653
                DOI: 10.1038/mp.2016.53
                PMC ID: 5378806
                PubMed ID: 27113994
                SO-VID: a7e24430-f59c-4e5f-9cf8-74ae5ffa6564
                Copyright © Copyright © 2016 Macmillan Publishers Limited
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 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-nc-nd/4.0/

                History
                Date received : 22 July 2014
                Date revision received : 28 February 2016
                Date accepted : 02 March 2016
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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