Abstract
BackgroundStressful life events influence the course of affective disorders, however, the mechanisms by which they bring about phenotypic change are not entirely known.MethodsWe explored the role of DNA methylation in response to recent stressful life events in a cohort of bipolar patients from the longitudinal PsyCourse study (n = 96). Peripheral blood DNA methylomes were profiled at two time points for over 850,000 methylation sites. The association between impact ratings of stressful life events and DNA methylation was assessed, first by interrogating methylation sites in the vicinity of candidate genes previously implicated in the stress response and, second, by conducting an exploratory epigenome-wide association analysis. Third, the association between epigenetic aging and change in stress and symptom measures over time was investigated.ResultsInvestigation of methylation signatures over time revealed just over half of the CpG sites tested had an absolute difference in methylation of at least 1% over a 1-year period. Although not a single CpG site withstood correction for multiple testing, methylation at one site (cg15212455) was suggestively associated with stressful life events (p < 1.0 × 10−5). Epigenetic aging over a 1-year period was not associated with changes in stress or symptom measures.ConclusionsTo the best of our knowledge, our study is the first to investigate epigenome-wide methylation across time in bipolar patients and in relation to recent, non-traumatic stressful life events. Limited and inconclusive evidence warrants future longitudinal investigations in larger samples of well-characterized bipolar patients to give a complete picture regarding the role of DNA methylation in the course of bipolar disorder.
Highlights
Stressful life events influence the course of affective disorders, the mechanisms by which they bring about phenotypic change are not entirely known
Investigation of the functional genomic distribution of the least stable cytosine-guanine dinucleotides (CpG) over time (|Δβ| ≥ 0.10) revealed the majority of CpGs fell within Open Seas, while 12 fell within CpG Islands, and the remaining in CpG Shores and Shelves (Fig. 2)
Suggestively significant, CpG site associated with total Life Events Questionnaire (LEQ) scores, mapping to POU6F2, which has been associated with several psychiatric traits as well as intelligence and educational attainment
Summary
Stressful life events influence the course of affective disorders, the mechanisms by which they bring about phenotypic change are not entirely known. Bipolar disorder (BD) remains an interesting candidate for neurobiological analyses owing to its heterogenous presentation and both genetic and environmental risk factors (Ludwig and Dwivedi 2016). Advances in technologies have supported high-throughput investigations of biological markers representative of environmental modulation of the genome. These biomarkers hold promise for stratifying symptom-based phenotypes and assessing the prognosis of individual patients (Kobeissy et al 2012). These biomarkers could contribute to a more accurate multi-level diagnostic framework which relies on biological measures to supplement clinical ratings of symptoms (Meana and Mollinedo-Gajate 2017)
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