Integrating psychological models with biological pathways in psychosis

精神分裂症是一种复杂的表型，其特征是现实扭曲，认知障碍，通常是阴性症状。双相情感障碍的特征是情绪高涨和低落，伴有或不伴有精神病特征。虽然精神分裂症和双相情感障碍的患病率相对较低，但它们造成了巨大的个人，经济和社会负担，与普通人群相比，患有这些疾病的人的预期寿命短15年。多基因风险计算的最新发展为研究潜在的遗传易感性开辟了一条新途径，同时排除了与特定候选基因选择相关的偏倚。多基因风险评分可以基于针对给定表型（个体的观察性状）进行的相当大的全基因组关联研究（GWAS）来计算，并将全基因组基因型数据总结为单个变量，该变量测量对疾病或正在研究的性状的遗传易感性。这样的多基因风险评分，反过来，可以与环境风险因素，增加精神分裂症或双相情感障碍的易感性和/或这些疾病的临床表现的严重程度一起研究。换句话说，有些人只有在遗传易感性和环境暴露（这里是儿童期不良事件）同时存在的情况下才会患上精神分裂症或双相情感障碍，但在遗传易感性或环境暴露单独存在的情况下不会患上精神分裂症或双相情感障碍。拟议的研究对患者护理和分层医学方法产生了影响：能够预测谁在儿童不良事件后更容易患上严重精神疾病，这对社会和个人都有巨大的影响。最近的研究表明，如果童年创伤得到预防，30%的严重精神疾病可以避免。此外，报告儿童不良事件的精神分裂症和双相情感障碍患者对治疗的反应较差，功能较差，端粒较短（加速衰老的标志物），突出了了解这一群体是否具有特定的生物学途径的关键需要，我们的目标是澄清作为本项目的一部分。从长远来看，这些知识可以通过关注受早期生活事件影响的特定生物途径以及疾病结果和衰老的预测模型来帮助改善专业医学。

Schizophrenia is a complex phenotype characterized by reality distortion, cognitive impairments, and often negative symptoms. Bipolar disorders are characterized by high and low mood with or without psychotic features. Although the prevalence of schizophrenia and bipolar disorders are relatively low, they account for a tremendous personal, economic, and societal burden and people with these disorders have 15 years shorter life expectancy compared to the general population. The recent development of polygenic risk calculations has opened a new avenue for studying the underlying genetic susceptibility while excluding biases related to the selection of specific candidate genes. A polygenic risk score can be computed based on sizeable genome-wide association studies (GWAS) performed for a given phenotype (an individual's observative traits) and summarises genome-wide genotype data into a single variable that measures genetic liability to the disorder, or the trait being studied. Such a polygenic risk score might, in turn, be studied together with environmental risk factors that increase the susceptibility to schizophrenia or bipolar disorders and/or the severity of the clinical expression of these disorders. In other words, that there are individuals who would develop schizophrenia or bipolar disorders only when both genetic liability and environmental exposure (here childhood adverse events) are present but would not develop schizophrenia or bipolar disorders when either genetic liability or environmental exposure is present alone. The proposed study has impact on patient care and a stratified medicine approach: To be able to predict who is more vulnerable of developing a severe mental illness following childhood adverse events can have huge impact on the society as well as for the individual. It has recently been shown that if childhood trauma was prevented, 30% of severe mental illness could be avoided. Moreover, patients with schizophrenia and bipolar disorders who report childhood adverse events respond less well to treatment, have poorer functioning, and shorter telomeres (a marker of accelerated ageing) highlighting the pivotal need to understand if this group has a specific biological pathway that could be pharmacological targeted which we aim to clarify as part of this project. In the long run this knowledge can help improve specialized medicine by focusing on specific biological pathways affected by early life events and prediction models for disease outcomes and ageing.