Our research

Our research group uses genomics to identify rare and common variation that underly reproductive traits, in order to understand the biological processes involved, find novel therapeutic targets and investigate the consequences of reproductive traits on health and disease. We are currently working in the following specific areas:

Reproductive ageing:  Ovarian reserve is established in fetal life and diminishes across the lifespan through atresia plus recruitment of follicles linked to menstruation. Two key events during this process are the start of menstruation, or menarche, and when the reserve becomes fully depleted at menopause. Timing of menarche and menopause is governed in part by multiple genetic factors and in our research we identify these factors and investigate how they impact ovarian reserve.

Reproductive health and disease: As ovarian reserve declines in the ovary, fertility also declines, with women becoming infertile approximately 10 years before menopause. Our research aims to identify potential new therapeutic options for infertility and also to be able to predict women at risk. The research also informs us about other ovary-centric disease such as primary ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS). We also have a longstanding interest in the aetiology of POI associated with the FMR1 premutaion variant.

Menopausal symptoms: Around 70% of women will experience symptoms as they go through menopause, which can be intolerable and often last for many years. We are interested in using genetics to better understanding what causes the various symptoms that have been linked to the menopause transition, with the aim of identifying new targets for therapies to treat them. 

Hormones: As ovarian reserve declines levels of hormones produced by the ovary change. The menstrual cycle is also regulated by hormones from the hypothalamic-pituitary axis. Our research investigates the role of reproductive hormones on health.

Impact of reproductive factors on health later in life: An individual’s genetic make-up is determined at birth and not influenced by lifestyle factors. We can therefore use genetic variants to make inferences about causal pathways to disease without the bias of confounders. We are interested in the impact of menopause timing and hormone levels on traits such as weight change, cancer risk, cardiovascular disease and diabetes. 

Funding

Improving future treatment options for menopausal symptoms by using genomics to understand aetiology.
MRC funding for 3 years from 1st February 2024, £800k.

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. Prompted by the increasing voice of women, there is currently a great deal of media attention on menopause, with 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 underpin 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 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 health conditions in large numbers of individuals is essential to be able to find genetic links. For menopausal symptoms 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. 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.

HEALTH-PM: Using genetics to understand the role of hormones in postmenopausal health.
Funded by UK Research and Innovation (UKRI) under the UK government’s Horizon Europe funding guarantee [grant number  EP/Y031970/1] to Dr Katherine Ruth for 5 years from 1st January 2024, £1.2 million

The health of older women poses significant challenges for future healthcare. Due to longer life-expectancy, women are living for longer after menopause and many will have multiple health conditions as they age, but historically women’s health research has been underfunded. Rates of disease increase rapidly after menopause, which is marked by substantial hormonal changes and life-changing symptoms for many women. We have limited understanding of the impact of hormonal changes across life on health after menopause.

HEALTH-PM will use state-of-the-art genetic epidemiology to test causal relationships of hormones with postmenopausal diseases and conditions, including menopausal symptoms. I will increase the size of existing genetic studies of hormones up to 10-fold through novel analyses of primary care health records linked to genetic data in 230K people, addressing the complexity of such data. For the first time, widespread genomewide analyses of postmenopausal disease will be performed, by combining health records data from hospitals, primary care and cancer registry with self-reported menopause status.

Given the possibility for modifying hormone levels with existing therapies, HEALTH-PM offers the potential to substantially improve women’s health.