Molecular Genetic Studies of Schizophrenia: Understanding Treatment Resistance and Outcomes to Inform Precision Psychiatry.

精神分裂症是一种严重的精神疾病，对个人和社会都有深远的影响。超过一半的SZ患者有长期的精神问题，80-90%的人失业，预期寿命缩短10-20年。近几十年来，这些结果没有改变。目前的抗精神病药物治疗通常会引起严重的不良反应，并且对约30%的SZ患者（称为治疗耐药SZ - TRS）的症状治疗无效。开发更有效和可接受的SZ治疗方法是患者的首要任务，但对于研究人员来说，这已被证明是一项重大挑战，因为我们对导致这种疾病的生物学过程知之甚少，更不知道是什么影响了好或坏的结果，对现有治疗的反应，我们还没有建立确定特定SZ患者群体的方法，这些人群可能从不同的治疗方法中受益。精准医学旨在解决这些问题，目的是开发更有针对性的治疗方法，最大限度地减少不良反应并改善患者的预后。在其他医学领域，遗传学是精准医学成功的核心。在过去的十年里，我们领导了国际研究，证实了遗传学对SZ风险的重要贡献。在这个项目中，我们将利用这些经验，并应用现代遗传学工具，通过研究TRS的遗传学基础和更广泛的患者预后，来推进精神病和SZ的精准医学方法。我们在与有精神病经历的患者协商后设计了研究方案，并通过这些讨论了解到，我们将把我们的项目重点放在TRS和患者优先考虑的其他结果上，包括（尽量减少）住院治疗、关系和职业功能。我们已经证明，基因对症状是否对治疗有反应起作用，我们现在将确定与TRS和其他结果相关的常见和罕见的遗传变异（风险等位基因）。我们需要非常大的数据集来实现这些目标，因此我们将汇集一个由国际研究人员组成的联盟，以及来自103,478名研究参与者的遗传和临床数据。我们将使用这些风险等位基因来识别与治疗结果相关的基因，并将与其他生物学数据集一起分析它们，以深入了解与这些治疗结果相关的生物学过程。此外，我们将进行分析，以确定可能影响TRS和改变结果的现有药物。如果能够区分哪些人需要新的或更密集的早期干预措施，哪些人有望通过现有干预措施取得良好效果，那么精准医疗的潜在影响可能是最大的。遗传风险评分代表影响一个人携带的条件或任何其他部分可遗传特征的遗传变异的总量，有时是特定模式。在其他常见疾病中，遗传风险评分开始有助于预测病程、结果和对特定治疗的需求。我们的目标是看看基于影响结果的DNA变异的遗传风险评分是否可以用来预测精神分裂症患者的结果，影响TRS和SZ的结果。我们相信，这些目标的完成将为精准医学在SZ的可行性提供重要见解，并将增强我们对TRS基础生物学和SZ患者预后的理解，突出潜在的新治疗靶点，并确定将从不同治疗方法中受益的精神病和SZ患者的不同群体。

Schizophrenia (SZ) is a severe psychiatric disorder that has a profound impact on the individual and society. Over half of people with SZ have long-term psychiatric problems, 80-90% are unemployed, and life expectancy is reduced by 10-20 years. These outcomes have not changed over recent decades. Current antipsychotic treatment often causes major adverse effects and is not effective in treating symptoms in around 30% of those with SZ (termed treatment resistant SZ - TRS). Developing more effective and acceptable treatments for SZ is a priority for patients but has proven a major challenge for researchers given we know little about the biological processes that cause the condition, and even less about what influences good or bad outcomes, response to existing treatments, and we do not have established ways of identifying specific groups of people with SZ that may benefit from different treatment approaches. Precision medicine seeks to address these issues with the aim of developing more targeted treatments, minimising adverse effects and improving patient outcomes. In other areas of medicine, genetics has been central to the success of precision medicine. We have led international research over the last decade that has confirmed the important contribution genetics makes to SZ risk. In this programme we will use this experience, and apply modern genetic tools, to advance precision medicine approaches in psychosis and SZ by investigating the genetic basis of TRS and wider patient outcomes. We have designed the research programme in consultation with patients who have lived experience of psychosis, and informed by these discussions, we will focus our projects on TRS and other outcomes prioritised by patients including (minimising) hospitalisation and relationship and occupational functioning. We have shown that genetics contributes to whether symptoms respond to treatment, and we will now identify both common and rare genetic variants (risk alleles) that are associated with TRS and the other outcomes.We require very large datasets to address these aims so we will bring together a consortium of international researchers and genetic and clinical data from 103,478 research participants. We will use these risk alleles to identify genes associated with treatment outcomes and will analyse them with other biological datasets to gain insights into the biological processes involved in these treatment outcomes. In addition, we will conduct analyses to identify existing medications that may impact TRS and alter outcomes. The potential impact of precision medicine is likely to be greatest if it is possible to differentiate between those who need new or more intensive early interventions and those who are expected to do well with existing interventions. Genetic risk scores represent the total amount, or sometimes the particular patterns, of genetic variants that influence a condition, or any other partly heritable characteristic, that a person carries. In other common illness, genetic risk scores are starting to be helpful in predicting course, outcomes, and the need for particular treatments. We aim to see if genetic risk scores based on the DNA variants that influence outcome can be used to predict those outcomes in people with schizophrenia, to influence TRS and outcomes in SZ. We believe completion of these aims will deliver important insights into the feasibility of precision medicine in SZ and will enhance our understanding of the fundamental biology of TRS and patient outcomes in SZ, highlighting potential novel treatment targets and identifying separate groups of people with psychosis and SZ who would benefit from different therapeutic approaches.