Improving future treatment options for menopausal symptoms by using genomics to understand aetiology
Lead Research Organisation:
UNIVERSITY OF EXETER
Department Name: Institute of Biomed & Clinical Science
Abstract
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.
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.
Technical Summary
Menopause is a fundamental physiological stage in female ageing, often accompanied by numerous symptoms, affecting daily life, including ability to work. Despite the prevalence and impact, the aetiology of symptoms is poorly understood and treatments are often untargeted. Hormone replacement therapy (HRT) is not effective for all symptoms, not appropriate for all women and avoided by many due to health risks. New targeted treatments are needed and could benefit >10 million women a year in the UK alone.
Genomics is a powerful approach for discovering aetiological mechanisms and identifying drug targets. Two independent genomic studies (one by Ruth/Murray) found the TACR3 gene associated with vasomotor symptoms. Antagonists of the TACR3 pathway ameliorated vasomotor symptoms in phase 2/3 clinical trials (one by Prague) and are expected to be licensed soon. This proof of principle illustrates the translational impact of a genomics approach and forms the basis of our research proposal.
Menopause affects sleep, mood, physical activity and sexual function in addition to the vasomotor traits. We will test all five domains in genome-wide analyses. Genomic data is available for many large population-based studies, but specific menopausal phenotypes are lacking. We will generate phenotypes in >700,000 women, including collecting new data for ~20,000 women aligned with the validated MENQOL questionnaire. Existing electronic health record and self-reported data will also be used. For vasomotor symtoms, we anticipate a five-fold increase in sample size compared to our previous study, which will result in a concomitant increase in genomic signals.
We will use genetic correlation, colocalization and Mendelian Randomisation analyses to provide aetiological insights into symptoms experienced during menopause. We will infer which have common or discrete causal mechanisms, transforming current understanding and future therapeutic options for millions of women worldwide.
Genomics is a powerful approach for discovering aetiological mechanisms and identifying drug targets. Two independent genomic studies (one by Ruth/Murray) found the TACR3 gene associated with vasomotor symptoms. Antagonists of the TACR3 pathway ameliorated vasomotor symptoms in phase 2/3 clinical trials (one by Prague) and are expected to be licensed soon. This proof of principle illustrates the translational impact of a genomics approach and forms the basis of our research proposal.
Menopause affects sleep, mood, physical activity and sexual function in addition to the vasomotor traits. We will test all five domains in genome-wide analyses. Genomic data is available for many large population-based studies, but specific menopausal phenotypes are lacking. We will generate phenotypes in >700,000 women, including collecting new data for ~20,000 women aligned with the validated MENQOL questionnaire. Existing electronic health record and self-reported data will also be used. For vasomotor symtoms, we anticipate a five-fold increase in sample size compared to our previous study, which will result in a concomitant increase in genomic signals.
We will use genetic correlation, colocalization and Mendelian Randomisation analyses to provide aetiological insights into symptoms experienced during menopause. We will infer which have common or discrete causal mechanisms, transforming current understanding and future therapeutic options for millions of women worldwide.
