Identifikation of epigenetic and cerebral markers linking early life adversities and adult anxiety disorder

焦虑症是最常见的精神障碍，在欧洲人群中12个月的患病率为14%。焦虑症的病因受遗传因素(遗传率估计：30-68%)和环境因素的影响。早年生活逆境对导致晚年焦虑症风险增加的病理生理过程的贡献一直被描述，但其潜在的生物学机制仍然知之甚少。正在出现的证据表明，表观遗传过程可能在连接早期生活逆境和焦虑症的生理反应中发挥作用。已经证明，焦虑症和早年的逆境都与大脑的明显变化有关。与迄今为止进行的众多基因成像研究相比，表观遗传过程对大脑连通性和激活模式的影响，以及更重要的是，它们在早期生活逆境和焦虑障碍发生之间的潜在中介作用仍有待阐明。因此，该研究项目的目的是：1)确定可以预测早期生活逆境个体中焦虑障碍发生的外周表观遗传生物标志物；2)评估早期生活逆境对焦虑障碍发生的表观遗传影响的脑相关性，以及它们作为表观遗传生物标记物和焦虑症之间的潜在介体的潜在功能。我们打算调查成年焦虑症患者和健康对照组的大量横断面队列中的早期生活逆境反应基因，以确定这些基因是否符合焦虑症的表观遗传生物标记物。此外，在成像表观遗传学的方法中，我们的目标是调查这些基因的表观遗传调控对大脑属性的影响，以定位早期生活逆境对焦虑症发展的表观遗传驱动效应的大脑介体。目前的方法将有助于更好地理解从早期生活逆境到成人焦虑症的神经生物学机制。此外，深入了解焦虑症的表观遗传调控可以在诊断、治疗和预防方面开辟新的途径，一组外围生物标记物可以用于在暴露于早期生活逆境后早期识别焦虑症的风险个体，这反过来可能有助于预防疾病的发生，因为可以迅速应用保护策略。

Anxiety disorders are the most common group of mental disorders with a twelve-month prevalence of 14% in the European population. The aetiology of anxiety is influenced by genetic (heritability estimates: 30 - 68%) as well as environmental factors. The contribution of early life adversities to pathopysiological processes which lead to an increased risk for anxiety disorders later in life has been consistently described, but the underlying biological mechanisms are still poorly understood. Evidence is emerging, that epigenetic processes might play a role in the physiological responses linking early life adversities and anxiety disorders. It has been demonstrated that both, anxiety disorders and early life adversities, are associated with distinct alterations of the brain. In contrast to numerous genetic imaging studies performed to date, the influence of epigenetic processes on cerebral connectivity as well as activation patterns and more importantly their potential mediating function between early life adversities and the occurrence of anxiety disorders remains to be elucidated. The aims of the proposed research project are therefore to i) identify peripheral epigenetic biomarkers which could predict the occurrence of anxiety disorders in individuals previously subjected to early life adversities and to ii) evaluate the cerebral correlates of epigenetic influences of early life adversities on the occurrence of anxiety disorders and their potential function as mediators between epigenetic biomarkers and anxiety disorders. We intend to investigate early life adversity-responsive genes in a large cross-sectional cohort of adult anxiety disorder patients and healthy control individuals to identify whether those genes qualify as epigenetic biomarkers of anxiety disorders. Furthermore, in an imaging epigenetics approach, we aim to investigate the influence of the epigenetic regulation of those genes on brain properties to localize cerebral mediators of epigenetic-driven effects of early life adversities on the development of anxiety disorders. The current approach will lead to a better understanding of the neurobiological mechanisms leading from early life adversities to adult anxiety disorders. Moreover, deeper insights into the epigenetic regulation of anxiety disorders could open new avenues in diagnoses, treatment, and prevention and a panel of peripheral biomarkers could be used to identify individuals at risk for anxiety disorders early after the exposure to early life adversities which in turn might contribute to the prevention of disease onset as protective strategies could be applied promptly.