Methylomic changes during conversion to psychosis

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.

The impact of epigenomic next‐generation sequencing approaches on our understanding of neuropsychiatric disorders

“…The need for longitudinal studies is therefore crucial in this field. Recently, Kebir et al have published a pioneering longitudinal prospective study, based on a cohort of help‐seeking young individuals enrolled for a 1‐year follow‐up. They showed that specific changes in DNA methylation are significantly different between converters to psychosis and non‐converters in SCZ, and occur in a clustered manner, preferentially in genes belonging to pathways relevant for psychosis (oxidative stress regulation, axon guidance and inflammatory pathways).…”

Epigenetic Modifications in Schizophrenia and Related Disorders: Molecular Scars of Environmental Exposures and Source of Phenotypic Variability

“…There is also an increasing number of genome-wide DNAm profiling studies of non-central nervous system (CNS) tissues such as blood (12,13,(48)(49)(50)(51)(52)(53) and saliva (54) ( Table 2). These can be further subdivided into longitudinal studies (48)(49)(50)(51)54), which assessed markers of conversion to psychosis in twins discordant for schizophrenia or high-risk individuals, and biomarker studies (12,13,52,53), which aim at uncovering biomarkers for schizophrenia in large cohorts. One advantage…”

“…Such longitudinal investigations, however, will require the use of easily accessible tissues such as peripheral blood, saliva, and olfactory epithelium (149). Even if epigenetic signatures in peripheral tissues might not necessarily capture disease-associated epigenetic changes occurring in the CNS (Tables 1 and 2), they can provide valuable information regarding the clinical course of schizophrenia, including conversion from a high-risk state to first-onset psychosis (50). The complementary use of animal models will further aid the interpretation of epigenetic findings obtained from longitudinal studies in humans.…”

Epigenetics applied to psychiatry: Clinical opportunities and future challenges

“…To address this issue, the use of analytical methods (e.g. causal inference testing and Mendelian randomization) or methodological approaches, such as the use of longitudinal cohorts would greatly help in deciphering the epigenetic contribution to disease. Finally, the use of adequate experimental models in rodents or in vitro systems, such as human inducible pluripotent cells derived from patients, in combination with an epigenome‐editing approach, could open new avenues to unravel the biological relevance of epigenetic changes.…”