Psychological and biological risk factors of burnout – Investigating epigenetic risk scores to understand the mechanistic pathways from work-related stress to burnout

根据世界卫生组织的数据，与工作相关的压力构成了越来越大的健康负担，并与西方社会的巨大成本有关。在这种情况下，一种关键的情况是工作倦怠--一种综合症，定义为情绪和身体疲惫，对工作的负面态度，以及对工作表现的负面评价，这是对长期不利的工作条件的反应。今天，是否能可靠地将倦怠与其他与压力相关的疾病区分开来，尤其是抑郁症，仍然存在争议。因此，职业倦怠特异性生物标志物的识别为理解从工作压力到职业倦怠的机制途径提供了一个有希望的途径，并为区分职业倦怠和抑郁提供了生物学依据。在这方面，DNA甲基化等表观遗传特征已经成为解释生活压力如何影响皮肤的核心机制。这一领域的第一个横断面发现现在需要前瞻性的纵向研究，理想的情况是包括高危和低危人群，并将对逆境和精神症状的细粒度评估与压力相关的生物标记物结合起来。为了解决这一差距，德累斯顿职业倦怠研究(DBS)是一项为期12年的大规模前瞻性队列研究，从心理、社会、临床和生物水平对职业倦怠进行年度评估。在这项提案中，我们现在的目标是实施表观遗传标记的评估，以补充和解释在DBS第一波期间获得的广泛的多水平数据。具体地说，我们的目标是测试这样的假设：(A)与工作相关的压力会引发表观遗传变化的纵向轨迹，(B)预测免疫/内分泌失调和倦怠症状。为此，我们将估计表观遗传风险分数(ERS)，这些表观遗传风险分数来自于先前关于应激可能导致随后的倦怠症状(包括皮质醇输出、炎症标志物和表观遗传衰老)的生物途径的表观基因组关联研究的汇总统计数据。使用这种ERS反映了一种强大的策略，将单个基因座的微小影响聚集在一起，然后可以用来有力地预测健康表型。其次，我们试图通过调查特定的ERS是否区分倦怠和抑郁症状，来为倦怠的区分效度提供生物学依据。鉴于与其他压力相关障碍相比，工作倦怠被认为首先依赖于职业逆境，我们将阐明：(C)与工作相关的压力是否会引起与非工作相关的压力源(D)相比的不同的ERS变化的纵向轨迹，从而区分疲惫和抑郁症状。确定职业倦怠的客观风险生物标记物和特定的病理后遗症可能为未来制定个性化的预防和治疗策略提供方向。

According to the World Health Organization, work‐related stress forms a growing health burden and relates to tremendous costs in Western societies. A crucial condition in this context is burnout—a syndrome defined by emotional and physical exhaustion, negative attitudes toward work and negative evaluation of ones work performance that develops in response to chronically adverse working conditions. Today, it remains controversial whether burnout can be reliably distinguished from other stress-related disorders, most notably depression. Consequently, the identification of burnout-specific biomarkers constitutes a promising approach to understand the mechanistic pathways from work-related stress to burnout and to provide a biologically-informed basis for the distinction between burnout and depression. In this regard, epigenetic signatures such as DNA methylation have emerged as central mechanisms explaining how life stress may get under the skin. First cross-sectional findings in this field now call for prospective, longitudinal studies that ideally include high and low risk populations and combine fine-grained assessments of adversity and psychiatric symptoms with stress-related biomarkers. To address this gap, the Dresden Burnout Study (DBS) was initiated as a large-scale, 12-year prospective cohort study with annual assessment of burnout on a psychological, social, clinical, and biological level. In this proposal, we now aim to implement the assessment of epigenetic markers to complement and interpret the extensive multi-level data that has been obtained during the first waves of the DBS. Specifically, we aim to test the hypotheses that (a) work-related stress provokes a longitudinal trajectory of epigenetic changes that (b) predict immunological/endocrine dysregulation and burnout symptoms. To this end, we will estimate epigenetic risk scores (ERS) derived from summary statistics of prior epigenome-wide association studies on biological pathway by which stress may contribute to ensuing burnout symptoms (including cortisol output, inflammatory makers and epigenetic aging). Use of such ERS reflects a powerful strategy to aggregate small effects of single loci, which can then serve to robustly predict health phenotypes. Second, we seek to provide biologically-informed evidence for burnout’s discriminant validity by investigating whether specific ERS differentiate between burnout and depressive symptoms or not. Given that burnout, as compared to other stress-related disorders, has been assumed to first and foremost dependent on occupational adversity, we will illuminate whether (c) work-related stress provokes distinct longitudinal trajectory of ERS changes compared to non-work related stressors (d) that could differentiate burnout from depressive symptoms. Identifying objective risk biomarkers and specific pathological sequelae of burnout may deliver directions for developing personalized prevention and treatment strategies in the future.