Methylomic changes during conversion to psychosis.
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.
Université Paris Descartes, PRES Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|CNRS, GDR3557-Institut de Psychiatrie, Paris, France.|Faculté de Médecine Paris Descartes, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Paris, France.
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Kebir
Université Paris Descartes, PRES Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|CNRS, GDR3557-Institut de Psychiatrie, Paris, France.|Faculté de Médecine Paris Descartes, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Paris, France.
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Chaumette
Université Paris Descartes, PRES Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|CNRS, GDR3557-Institut de Psychiatrie, Paris, France.|Faculté de Médecine Paris Descartes, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Paris, France.
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Rivollier
CNRS, UMR7216 Épigénétique et Destin Cellulaire, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Département Hospitalo-Universitaire DHU PROTECT, Paris, France.
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Miozzo
Université de Montréal, Beaulieu-Saucier Pharmacogenomics Center, Montréal Heart Institute, Montréal, QC, Canada.
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Lemieux Perreault
Université de Montréal, Beaulieu-Saucier Pharmacogenomics Center, Montréal Heart Institute, Montréal, QC, Canada.
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Barhdadi
Université de Montréal, Beaulieu-Saucier Pharmacogenomics Center, Montréal Heart Institute, Montréal, QC, Canada.
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Provost
Université Paris Descartes, PRES Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|CNRS, GDR3557-Institut de Psychiatrie, Paris, France.|Faculté de Médecine Paris Descartes, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Paris, France.
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Plaze
Université Paris Descartes, PRES Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|CNRS, GDR3557-Institut de Psychiatrie, Paris, France.|Faculté de Médecine Paris Descartes, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Paris, France.
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Bourgin
Université Paris Descartes, PRES Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|CNRS, GDR3557-Institut de Psychiatrie, Paris, France.|Faculté de Médecine Paris Descartes, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Paris, France.
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Gaillard
CNRS, UMR7216 Épigénétique et Destin Cellulaire, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Département Hospitalo-Universitaire DHU PROTECT, Paris, France.
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Mezger
Université de Montréal, Beaulieu-Saucier Pharmacogenomics Center, Montréal Heart Institute, Montréal, QC, Canada.
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Dubé
Université Paris Descartes, PRES Université Paris Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|INSERM, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, UMR S 894, Paris, France.|CNRS, GDR3557-Institut de Psychiatrie, Paris, France.|Faculté de Médecine Paris Descartes, Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Paris, France.
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Krebs
D000293:Adolescent; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics; D057890:Epigenomics / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D011618:Psychotic Disorders / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
C524366:GSTM5 protein, human; D005982:Glutathione Transferase