Improving future treatment options for menopausal symptoms by using genomics to understand aetiology

随着女性进入更年期，荷尔蒙水平发生变化，月经停止。更年期通常伴有潮热/盗汗、睡眠不安和情绪变化等症状。对于大约十分之一的女性来说，这些症状会持续多年，并影响她们的生活质量、工作能力和心理健康。目前，包括女明星在内的越来越多的女性希望强调更年期的重要性并消除禁忌，这促使媒体对更年期进行了大量关注。尽管如此，对更年期症状的研究相对有限。提供给女性的一些建议并不总是基于有力的科学证据，比如使用睾丸激素治疗性欲低下和疲劳。潮热可以通过激素替代疗法（HRT）重新平衡激素水平来成功治疗，但这种治疗方法并不推荐给所有人。其他症状似乎不太有效的治疗HRT，如睡眠障碍。由于担心副作用，包括增加乳腺癌的风险，一些女性更喜欢避免激素替代疗法。目前还没有研究为什么女性在更年期会有不同的症状，或者是什么原因导致了这些症状。我们想要回答这些问题，这样我们就可以找到更好的治疗更年期症状的方法。研究我们基因的差异为理解导致疾病和健康状况的生物过程提供了一个独特的机会。发现与某种疾病的基因联系通常会揭示真正的原因，因为我们的基因在我们的一生中不会因环境或生活方式而改变。现在全世界有成千上万的人在研究中收集了基因数据，其中大部分数据以最低的成本提供给研究人员。这些研究也有关于参与者的健康和生活方式的信息，许多研究还可以获得他们的健康记录。我们之前已经处理过很多这样的数据集，包括对20多万名女性的研究，这帮助我们了解卵巢是如何衰老的。我们也开始用遗传学来研究绝经期潮热的原因，研究对象是来自英国生物银行的92000名女性。我们发现了一种与一种新疗法直接相关的基因，这种疗法目前正在大型临床试验中作为替代激素替代疗法进行测试。这证明我们的方法很有效，所以我们想用它来研究更年期的其他症状。大量个体在更年期前后出现的症状的详细信息对于能够找到遗传联系至关重要。目前，这些信息通常是不可用的。因此，我们将以一种标准化的方式收集有关更年期症状的信息，结合三种方法：(i)制定一项定制调查，发给研究参与者；（ii）利用某些研究已掌握的现有资料；（iii）使用与研究参与者相关的电子医疗记录。通过这种方法，我们预计总共将有超过70万名女性的数据，这将最大限度地提高发现新的遗传联系的机会。我们还将使我们生成的数据可供其他研究人员使用，并在未来继续发展。对于潮热，我们预计能够识别5-10个新基因。这将增加我们对引起潮热的原因的理解，并为我们指明可能用于治疗女性潮热的新药的方向。通过了解其他症状的原因，我们将能够评估哪些可以用类似的药物治疗，哪些需要替代疗法。这项研究涉及一个重要的、研究不足的医学领域，引起妇女的重大关注，并具有重要的社会影响。

As women go through menopause, hormone levels change and periods stop. Menopause is often accompanied by symptoms, such as hot flushes/night sweats, disturbed sleep, and mood change. For about 1 in 10 women these symptoms can continue for many years and affect their quality of life, ability to work and mental health. There is currently a great deal of media attention on menopause, prompted by the increasing voice of women, including female celebrities, wanting to highlight its importance and remove taboos. Despite this, research into the symptoms experienced around menopause has been relatively limited. Some advice being offered to women is not always based on robust scientific evidence, such as using testosterone to treat low sex drive and tiredness. Hot flushes can be successfully treated by re-balancing hormone levels with hormone replacement therapy (HRT), but this treatment is not recommended for everyone. Other symptoms seem to be less effectively treated by HRT, for example sleep disturbance. Some women prefer to avoid HRT due to fears regarding side effects including increased risk of breast cancer. Research has not yet studied why women have different symptoms in the menopause, or what causes all of them. We want to answer these questions so that we can find better treatments for symptoms experienced during menopause. Studying differences in our genes provides a unique opportunity to understand the biological processes that cause diseases and health conditions. Finding a genetic link with a condition generally reveals a true cause, because our genes are not changed over our lifetime by the environment or our lifestyle. There are now hundreds of thousands of people who have had genetic data collected in studies across the world and much of this data is available to researchers at minimal cost. These studies also have information about the health and lifestyle of the participants and many also have access to their health records. We have have worked with many of these data sets previously, including a study of more than 200,000 women which helped us understand how the ovary ages. We have also started to use genetics to investigate the causes of menopausal hot flushes in a study of 92,000 women from the UK Biobank. We found a gene that is directly linked to a new treatment that is currently being tested in large clinical trials as an alternative to HRT. This proves our approach works well, so we want to use it to study other symptoms of the menopause.Detailed information about symptoms occuring around menopause in large numbers of individuals is essential to be able to find genetic links. Currently, this information is often not available. Therefore, we will collect information about symptoms that occur during menopause in a standardised way, combining three approaches: (i) develop a bespoke survey to send out to study participants; (ii) use existing information already held by some studies; and (iii) use electronic healthcare records that are linked to study participants. With this approach we expect to have data from over 700,000 women in total, which will maximise the chance of finding new genetic links. We will also make the data we generate available to other researchers to use and build on in the future. For hot flushes we anticipate being able to identify 5-10 new genes that are involved. This will increase our understanding of what causes hot flushes and point us in the direction of new drugs that might be used to treat women who experience them. By understanding the causes of other symptoms we will be able to assess which might be treated by similar drugs, and which will need alternative therapies. The study addresses an important and under-researched area of medicine, of significant concern to women and with important societal implications.