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，有或没有精神病特征。虽然精神分裂症和双相情感障碍的患病率相对较低，但它们会给个人、经济和社会带来巨大的负担，而且与普通人群相比，这些障碍患者的预期寿命要短15岁。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的途径，同时排除了与特定候选基因选择有关的偏差。多基因风险分数可以基于对给定表型(个人的可观察特征)进行的大规模全基因组关联研究(GWAS)来计算，并将全基因组的基因型数据汇总为单一变量，该变量衡量疾病或正在研究的特征的遗传易感性。这样的多基因风险得分可能会与增加精神分裂症或双相情感障碍易感性和/或这些障碍临床表现的严重程度的环境风险因素一起研究。换句话说，只有当遗传责任和环境暴露(这里是儿童不良事件)都存在时，才会有个人患上精神分裂症或双相情感障碍，但当遗传责任或环境暴露单独存在时，不会患上精神分裂症或双相情感障碍。这项拟议的研究对患者护理和分层医学方法产生了影响：能够预测谁更容易在童年不良事件后患上严重精神疾病，可能会对社会和个人产生巨大影响。最近的研究表明，如果预防童年创伤，30%的严重精神疾病是可以避免的。此外，报告童年不良事件的精神分裂症和双相情感障碍患者对治疗反应不佳，功能较差，端粒较短(加速衰老的标志)，突显了了解这一群体是否有可能成为药理学靶向的特定生物路径的关键需要，我们的目标是作为这个项目的一部分来澄清这一点。从长远来看，这一知识可以通过专注于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进专业医学。

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.