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

据世界卫生组织称，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相关。在这种情况下，一个关键的条件是倦怠——这是一种由情绪和身体疲惫、对工作的消极态度和对工作表现的消极评价所定义的综合症，是对长期不利工作条件的反应。如今，是否能可靠地将倦怠与其他与压力相关的疾病（最明显的是抑郁症）区分开来仍存在争议。因此，确定倦怠特异性生物标志物是一种很有希望的方法，可以理解从工作压力到倦怠的机制途径，并为区分倦怠和抑郁提供生物学依据。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进入皮肤的核心机制。这一领域的第一个横断面研究结果现在需要前瞻性的纵向研究，最好包括高风险和低风险人群，并将逆境和精神症状的细粒度评估与压力相关的生物标志物结合起来。为了解决这一差距，德累斯顿职业倦怠研究（DBS）是一项大规模的、为期12年的前瞻性队列研究，每年对心理、社会、临床和生物学水平的职业倦怠进行评估。在本提案中，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的第一波中获得的广泛的多层次数据。具体来说，我们的目标是验证以下假设：(a)工作压力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，我们将评估表观遗传风险评分（ERS），该评分来源于对应激可能导致随后的倦怠症状（包括皮质醇输出、炎症因子和表观遗传衰老）的生物学途径的全表观基因组关联研究的汇总统计。这种ERS的使用反映了一种强大的策略，可以聚集单个位点的小影响，然后可以用于稳健地预测健康表型。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，为倦怠的区别效度提供生物学依据。考虑到与其他压力相关的疾病相比，职业倦怠被认为首先依赖于职业逆境，我们将阐明(c)与非工作相关的压力源相比，工作压力是否会引起ERS变化的明显纵向轨迹(d)是否可以区分倦怠和抑郁症状。确定职业倦怠的客观风险生物标志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.