The role of environmental stress and DNA methylation in the longitudinal course of bipolar disorder

Abstract

Background: Stressful life events influence the course of affective disorders, however, the mechanisms by which they bring about phenotypic change are not entirely known. Methods: We 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. Results: Investigation 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. Conclusions: To 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.

The Impact of Psychosocial Stress from Life Trauma and Racial Discrimination on Epigenetic Aging—A Systematic Review

“…Due to the limited number of the studies in the topic area, we tried to include as many studies as possible from the screening. This resulted in including studies about participants with certain conditions such as depression (Han et al, 2018) or bipolar disorder (Comes et al, 2020). The mean sample size was 458 and the sample sizes ranged from 96 to 1163.…”

“…As shown in Table 2, six studies explored the relationship between life trauma or life stress and DNAm age (Boks et al, 2015; Brody et al, 2016; Comes et al, 2020; Katrinli et al, 2020; Wolf et al, 2018, 2019a). One study focused on combat trauma (Boks et al, 2015) and two evaluated life stress (Brody et al, 2016; Comes et al, 2020). Among the six studies, two (33.3%) reported positive relationships (Boks et al, 2015; Katrinli et al, 2020), one of which assessed the effects of combat trauma.…”

“…Six studies were predominantly male (Boks et al, 2015;Mehta et al, 2018;Wolf et al, 2018Wolf et al, , 2019aWolf et al, , 2019bYang et al, 2020), and remaining studies included 33-70% females (Brody et al, 2016;Comes et al, 2020;Han et al, 2018;Katrinli et al, 2020). Six studies included predominantly participants of European ancestry (Boks et al, 2015;Comes et al, 2020;Wolf et al, 2018Wolf et al, , 2019aWolf et al, , 2019bYang et al, 2020), and two were completed with primarily Black or African American participants (Brody et al, 2016;Katrinli et al, 2020). Four studies evaluated the experiences of male veterans (Boks et al, 2015;Mehta et al, 2018;Wolf et al, 2018;Yang et al, 2020).…”

“…Six studies used a cross-sectional design (Han et al, 2018;Katrinli et al, 2020;Mehta et al, 2018;Wolf et al, 2018Wolf et al, , 2019bYang et al, 2020), and one of these studies completed longitudinal analysis among a subset of individuals (n = 26; Yang et al, 2020). Four studies used longitudinal study design analyzing two samples collected 1-3 years apart (Boks et al, 2015;Comes et al, 2020;Wolf et al, 2019a;Yang et al, 2020). They examined the changes of various stress from traumatic life events, life stress, childhood trauma, and PTSD, with the change of DNAm age.…”

“…Three types of epigenetic clock were used: Horvath, Hannum, and GrimAge. Horvath's clock was most frequently used (60% of studies) (Boks et al, 2015;Comes et al, 2020;Han et al, 2018;Mehta et al, 2018;Wolf et al, 2019aWolf et al, , 2019b. One study modified the clock calculation, but indicated their approach was similar to Horvath's method (Han et al, 2018).…”