Uncovering Sex-Specific Biological Mechanisms of Depression: Insights from Large-Scale Data Analysis

揭示抑郁症的性别特异性生物学机制：大规模数据分析的见解

• 批准号: MR/Y011112/1
• 负责人: David Mark Howard
• 金额: $ 242.02万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY011112%2F1
• 关键词: Uncovering; Sex; Specific; Biological; Mechanisms

Depression causes feelings of low mood and a loss of interest in things that used to be enjoyable. One in six people suffer from depression during their lifetime. However, women are twice as likely to have depression compared to men. There are likely to be a number of reasons for this difference, although we don't yet fully understand them. Biology is likely to play an important role in this difference between the sexes and my research will explore this in more detail.My previous work has shown that different genes are involved in female depression compared to depression in men. This previous research used data from nearly 300,000 people. The new work will examine millions of people and will greatly improve on what we can detect. The results from this first project will also be used to identify the sections of DNA that might be good targets for antidepressant drugs. If we can discover which drugs are likely to work based on someone's DNA, we can also then figure out which drugs might not work. We will then test this using the UK Biobank. The UK Biobank has DNA information and is linked up to past prescription records. So, we can check whether the people we think won't respond to a drug based on their DNA actually end up switching treatments. It is hoped this work will help doctors decide on the best medication for each patient with depression.Some DNA is inherited via the sex chromosomes (known as the X and Y chromosomes). However, the sex chromosomes are often overlooked in depression research even though they might contain useful information. Genes are turned on and off at different points during our lives and so this may also happen when someone becomes depressed. Using the largest data available we will see if we can find evidence of genes on the sex chromosomes being turned on or off due to depression. Females get two X chromosomes, one inherited from their mother and one from their father. In every cell in the female body, one of these X chromosomes is inactivated. This is normally a random process. So, half of cells have the X chromosome from their mother inactivated, and the other half of cells have the X chromosome inherited from their father inactivated. However, in some women there are more cells that have either the X chromosome from their mother or father inactivated, which is known as skewness. This skewness has been observed in other mental health conditions and we will look at whether it occurs in depression.There are molecules that circulate in our blood that might put us at greater or lower risk of depression. We will look at new molecular data from the UK Biobank to identify those molecules that differ for people with depression. We will do this separately for women and men using state-of-the-art methods. This will provide us with molecular profiles for depression. We will then test whether any molecules differ between men and women in their link with depression. The final project will look at whether changes in particular molecules lead to depression, or these changes are because of having depression.Each of these projects will provide us with further clues about the biology of depression. The hope is that this information will identify the best treatment for those with the disorder.

抑郁会引起情绪低落的感觉，并失去对过去令人愉悦的事物的兴趣。六分之一的人一生都患有抑郁症。但是，与男性相比，女性患抑郁症的可能性是两倍。尽管我们尚未完全理解它们，但可能会有许多原因。生物学在性别之间的这种差异中可能发挥重要作用，而我的研究将更详细地探讨这一点。我以前的工作表明，与男性抑郁症相比，女性抑郁症的不同基因涉及女性抑郁症。这项先前的研究使用了来自近30万人的数据。新工作将检查数百万人，并将大大改善我们可以发现的东西。第一个项目的结果还将用于确定可能是抗抑郁药物的良好靶标的DNA部分。如果我们可以根据某人的DNA发现哪些药物可能起作用，那么我们还可以弄清楚哪些药物可能不起作用。然后，我们将使用英国生物库来对其进行测试。英国生物库有DNA信息，并链接到过去的处方记录。因此，我们可以检查我们认为我们认为基于DNA的药物的人是否最终会改用治疗方法。希望这项工作能够帮助医生为每位抑郁症患者做出最好的药物。某些DNA是通过性染色体（称为X和Y染色体）遗传的。但是，在抑郁症研究中，性染色体通常会忽略它们，即使它们可能包含有用的信息。在我们一生中，基因在不同的位置打开和关闭，因此，当某人变得沮丧时，这也可能发生。使用最大的数据，我们将查看是否可以找到有关抑郁症的性别染色体基因的证据。女性获得了两个X染色体，其中一种是从母亲那里继承的，另一个是从父亲那里继承的。在女性体内的每个细胞中，这些X染色体之一都是灭活的。这通常是一个随机过程。因此，一半的细胞从母亲失活的X染色体中，另一半细胞的X染色体是从父亲灭活的。但是，在某些女性中，有更多的细胞从父母灭活的父亲中染色体X染色体，这被称为偏度。在其他心理健康状况中已经观察到了这种偏度，我们将研究它是否发生在抑郁症中。在血液中流通的分子可能使我们处于抑郁症的风险更大或更低。我们将研究来自英国生物库的新分子数据，以确定那些抑郁症患者不同的分子。我们将使用最先进的方法为男女分开做。这将为我们提供用于抑郁症的分子特征。然后，我们将测试男性和女性与抑郁症联系在一起的任何分子是否有所不同。最终项目将研究特定分子的变化是否导致抑郁症，或者这些变化是由于抑郁症。这些项目的每个项目将为我们提供有关抑郁症生物学的进一步线索。希望这些信息将确定患有该疾病患者的最佳治疗方法。