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

抑郁会导致情绪低落，对曾经令人愉快的事情失去兴趣。每六个人中就有一个在一生中遭受抑郁症的折磨。然而，与男性相比，女性患抑郁症的可能性是男性的两倍。造成这种差异的原因可能有很多，尽管我们还没有完全理解这些原因。生物学很可能在这种性别差异中扮演着重要的角色，我的研究将更详细地探索这一点。我之前的工作表明，与男性抑郁相比，女性抑郁涉及的基因不同。这项先前的研究使用了近30万人的数据。这项新工作将检查数百万人，并将极大地改进我们可以检测到的东西。第一个项目的结果还将用于识别可能成为抗抑郁药物良好靶点的DNA片段。如果我们可以根据某人的DNA发现哪些药物可能有效，那么我们也可以找出哪些药物可能不起作用。然后，我们将使用英国生物库对此进行测试。英国生物库拥有DNA信息，并与过去的处方记录联系在一起。因此，我们可以根据他们的DNA来检查那些我们认为对药物没有反应的人是否真的会改变治疗方法。希望这项工作能帮助医生为每个抑郁症患者选择最好的药物。一些DNA是通过性染色体(称为X和Y染色体)遗传的。然而，在抑郁症研究中，性染色体经常被忽视，尽管它们可能包含有用的信息。基因在我们生命中的不同时刻被开启和关闭，所以当一个人变得抑郁时也可能发生这种情况。使用现有的最大数据，我们将看看是否可以找到性染色体上的基因因抑郁而打开或关闭的证据。女性有两条X染色体，一条遗传自母亲，另一条遗传自父亲。在女性体内的每一个细胞中，这些X染色体中的一个是失活的。这通常是一个随机过程。因此，一半的细胞使其母亲的X染色体失活，另一半的细胞使从其父亲那里遗传的X染色体失活。然而，在一些女性中，有更多的细胞具有来自母亲或父亲的X染色体失活，这被称为偏斜。这种偏斜在其他精神健康状况中也被观察到，我们将观察它是否发生在抑郁中。在我们的血液中循环的一些分子可能会让我们处于抑郁的更高或更低的风险中。我们将查看来自英国生物库的新分子数据，以确定那些与抑郁症患者不同的分子。我们将使用最先进的方法分别为女性和男性做这项工作。这将为我们提供抑郁症的分子图谱。然后，我们将测试男性和女性与抑郁症之间的联系是否有任何不同的分子。最后一个项目将考察特定分子的变化是否会导致抑郁，或者这些变化是因为抑郁。这些项目中的每一个都将为我们提供关于抑郁生物学的进一步线索。人们希望这些信息将为那些患有这种疾病的人找到最佳的治疗方法。

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.