Informing precision psychiatry through developing comprehensive genomic models of mental health disorders

通过开发精神健康疾病的综合基因组模型为精准精神病学提供信息

• 批准号: MR/T018712/1
• 负责人: Elliott Rees
• 金额: $ 115.68万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT018712%2F1
• 关键词: Informing; precision; psychiatry; through; developing

Mental health disorders have a dramatic impact on the wellbeing of affected individuals and their families, and as a result are a leading cause of disability worldwide. Each year in the UK, mental illness affects around 13.5 million people and places a significant burden on the economy through direct (health care) and indirect (lost work and productivity) costs. Although the exact causes of mental health disorders are unknown, a wide range of factors have been found to contribute to their development. For example, many genes are known to significantly influence the development of schizophrenia, and social factors, such as childhood adversity, are also known to have a role. However, no individual cause is by itself necessary or sufficient for the development of mental illness. Moreover, different combinations of risk factors are observed in individuals with the same diagnosis, while the same risk factors are often shared across different disorders. This complexity has made it challenging to study mental health disorders, and a poor understanding of their biological causes has prevented the development of new or more effective treatments. There is also an absence of biologically validated markers for diagnosing patients and identifying individuals who could benefit from more personalised treatments. Another barrier to progress in these areas is that no single type of data can capture all risk factors that influence the development of mental illness. My research aims to address this challenge by integrating different types of biomedical data produced from the same individuals, and developing new methods to simultaneously study the full range of risk factors that contribute to mental ill health. I will initially bring together different types of genetic data, each designed to capture unique forms of genetic variation, from the world's largest schizophrenia samples. This will allow me to provide the most thorough characterisation of genetic variation in schizophrenia to date. I will use these data to discover new risk genes, which will help illuminate the biological causes of schizophrenia. It will also provide molecular targets for the development of new medicines.The symptoms of schizophrenia can vary greatly from person to person, and individuals with the disorder do not always respond to the same treatments. My research aims to identify the genes that influence this variation, which could lead to the development of biomarkers that can be used for providing personalised programmes of treatment. I will also uncover why some genes influence the development of more than one psychiatric disorder, and identify genetic factors that are unique to a specific mental illness. This will be extremely important if genetics is to be used clinically to improve the prediction, diagnosis and prognosis of mental health disorders. My research will also identify genetic factors that protect against the development of psychiatric disorders, as well as explain why some individuals with potent genetic risk factors do not experience mental illness. Understanding this latter phenomenon could point towards new intervention strategies to help prevent people from developing a mental health disorder.The long-term goal of my research is to understand how genes that influence the development of mental health disorders operate alongside additional biological and environmental risk factors. This will provide a more comprehensive understanding of the causes and risks associated with mental illness. I will work closely with clinical colleagues in the NHS and partners in industry to ensure my research is translated into new ways to improve the wellbeing of individuals affected by mental ill health.

精神健康障碍对受影响的个人及其家人的福祉有重大影响，因此是全世界残疾的主要原因。在英国，精神疾病每年影响约1350万人，并通过直接(医疗保健)和间接(失去工作和生产力)成本给经济带来重大负担。尽管精神健康障碍的确切原因尚不清楚，但已发现许多因素对其发展起到了促进作用。例如，已知许多基因显著影响精神分裂症的发展，社会因素，如童年的逆境，也已知有作用。然而，没有任何单独的原因本身对精神疾病的发展是必要或充分的。此外，在同一诊断的个体中观察到不同的风险因素组合，而相同的风险因素往往在不同的疾病中共享。这种复杂性使精神健康障碍的研究具有挑战性，而对其生物学原因的缺乏理解阻碍了新的或更有效的治疗方法的开发。也没有经过生物验证的标记来诊断患者和识别可以从更个性化的治疗中受益的个人。在这些领域取得进展的另一个障碍是，没有任何单一类型的数据可以涵盖影响精神疾病发展的所有风险因素。我的研究旨在通过整合来自相同个人的不同类型的生物医学数据来应对这一挑战，并开发新的方法来同时研究导致精神疾病健康的各种风险因素。我首先将从世界上最大的精神分裂症样本中收集不同类型的基因数据，每一种数据都旨在捕获独特形式的基因变异。这将使我能够提供迄今为止精神分裂症基因变异的最全面的特征。我将利用这些数据发现新的风险基因，这将有助于阐明精神分裂症的生物学原因。它还将为新药的开发提供分子靶点。精神分裂症的症状因人而异，而且患有精神分裂症的人对相同的治疗并不总是有反应。我的研究旨在识别影响这种变异的基因，这可能会导致生物标记物的开发，这些生物标记物可以用于提供个性化的治疗方案。我还将揭示为什么某些基因会影响不止一种精神疾病的发展，并确定特定精神疾病特有的遗传因素。如果要在临床上使用遗传学来改善精神健康障碍的预测、诊断和预后，这将是极其重要的。我的研究还将确定防止精神疾病发展的遗传因素，并解释为什么一些具有潜在遗传风险因素的人不会经历精神疾病。理解后一种现象可以指出新的干预策略，以帮助防止人们患上心理健康障碍。我研究的长期目标是了解影响心理健康障碍发展的基因是如何与其他生物和环境风险因素一起作用的。这将使人们更全面地了解与精神疾病相关的原因和风险。我将与NHS的临床同事和行业合作伙伴密切合作，确保我的研究转化为新的方法，以改善受精神疾病影响的个人的福祉。

项目成果

Clinical and genotypic analysis in determining dystonia non-motor phenotypic heterogeneity: a UK Biobank study.

• DOI: 10.1007/s00415-022-11307-4
• 发表时间: 2022-12
• 期刊: JOURNAL OF NEUROLOGY
• 影响因子: 6
• 作者: Wadon, Megan E.;Fenner, Eilidh;Kendall, Kimberley M.;Bailey, Grace A.;Sandor, Cynthia;Rees, Elliott;Peall, Kathryn J.
• 通讯作者: Peall, Kathryn J.

Genomic findings in schizophrenia and their implications.

• DOI: 10.1038/s41380-023-02293-8
• 发表时间: 2023-09
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Owen, Michael J.;Legge, Sophie E.;Rees, Elliott;Walters, James T. R.;O'Donovan, Michael C.
• 通讯作者: O'Donovan, Michael C.

Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations.

• DOI: 10.1038/s41467-021-25532-4
• 发表时间: 2021-09-09
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Rees E;Creeth HDJ;Hwu HG;Chen WJ;Tsuang M;Glatt SJ;Rey R;Kirov G;Walters JTR;Holmans P;Owen MJ;O'Donovan MC
• 通讯作者: O'Donovan MC

Ultrarare Coding Variants and Cognitive Function in Schizophrenia.

• DOI: 10.1001/jamapsychiatry.2022.2289
• 发表时间: 2022-10-01
• 期刊: JAMA PSYCHIATRY
• 影响因子: 25.8
• 作者: Creeth, Hugo D. J.;Rees, Elliott;Legge, Sophie E.;Dennison, Charlotte A.;Holmans, Peter;Walters, James T. R.;O'Donovan, Michael C.;Owen, Michael J.
• 通讯作者: Owen, Michael J.

Family-based analysis of the contribution of rare and common genetic variants to school performance in schizophrenia.

• DOI: 10.1038/s41380-023-02013-2
• 发表时间: 2023-05
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Rammos, Alexandros;Kirov, George;Hubbard, Leon;Walters, James T. R.;Holmans, Peter;Owen, Michael J.;O'Donovan, Michael C.;Rees, Elliott
• 通讯作者: Rees, Elliott