Unlocking fertility in women via human omics data

Dr Staša Stanković, University of Belgrade, Faculty of Mathematics, Serbia

Abstract: Menopause timing is highly variable, having a direct effect on reproductive lifespan, fertility and health outcomes in later life. Endocrine and imaging tests only record changes in ovarian function that have already taken place, thus disabling early prediction and identification of women with reduced reproductive lifespan, such as primary ovarian insufficiency (menopause below 40). Human genetic studies have attempted to overcome this problem by identifying genetic markers associated with menopause timing and fertility. Using data from large scale population studies, including UK Biobank, 23&Me and deCODE Genetics, we assessed both common and rare genetic variation that influence menopause timing in women. Our work on common genetic variants led to the discovery of over 300 genetic signals (Nature, 2021) that influence the age women begin menopause and the first evidence of our ability to, through gene manipulation in a mouse model, extend reproductive lifespan by 25% and improve fertility. The power of this information is that in the future we may be able to build the first genetic prediction test that will inform every woman about the timing of her menopause. In addition, these findings are critical as improved knowledge of the underlying mechanisms may also allow their manipulation, more specifically halting or temporizing the process of the loss of ovarian follicles and provide a new direction for therapeutic approaches that might seek to treat infertility. To assess the impact of rare damaging variants on age at natural menopause, we queried whole-exome sequencing data for 106,973 post-menopausal women in UK Biobank and implicated novel genes with effect sizes up to 6 times larger than previously discovered (under review, Nature). Finally, we found that genetic susceptibility to earlier ovarian ageing in women increases de novo mutation rate in their offspring. This provides direct evidence that female mutation rate is heritable and highlights a mechanism of the maternal genome influencing child health, which could have direct implications for the health of future generations given the link between de novo mutations and disease risk. Our study provides biological insights into reproductive ageing by increasing the number of implicated genes with a potential to inform experimental studies seeking to identify new therapies that enhance reproductive function and preserve fertility.

Biography: Dr Staša Stanković is a geneticist and bioinformatician with a PhD in Reproductive Genomics from the University of Cambridge. Her work is focused on deciphering the genetic architecture of reproductive ageing and fertility using large-scale population omics data, and their link to later life health outcomes in women. The work by Staša and her collaborators led to the discovery of genetic signals that influence the age women begin menopause and the first evidence of the ability to, through gene manipulation in mouse model, extend reproductive lifespan and improve fertility. Staša and her collaborators are using these ground-breaking findings to embark on the commercialisation journey towards the development of prediction tests and next generation therapeutics for reproductive disorders.

Prior to her PhD, Staša was awarded an MPhil in Medical Science from the University of Cambridge, Wellcome Trust Sanger Institute and dual BSc in Biomedical Sciences from the University of Oxford and Oxford Brookes University. Staša was also part of Congenica, genomic data analysis company, where she contributed to the development of “Congenica Neuro”, new generation product for the tailored genomic analysis of individuals with neurodevelopmental diseases, enabling clinicians to provide >20X faster diagnosis.

She was a founder of Innovation Forum Serbia with an aim to build a mechanism that will support the generation and development of Serbian healthcare startup ecosystem, and bridge the gap between academia, industry, policy makers and investors. In the ecosystem where this concept was unexplored at the time, she managed to attract strategic and financial support by leading governmental (UK and Serbian Government, NHS) and industrial (Roche, AstraZeneca, Microsoft etc.) institutions to pioneer crucial systematic changes. This enabled her to establish the first ever healthcare accelerator programme in Serbia, ‘IMAGINE IF!’ in collaboration with Science Technology Park Belgrade.

She is also a business consultant, where she built numerous digitalisation and innovation strategies for major pharmaceutical and governmental institutions. Based on her impact, she was awarded ‘McKinsey&Company Next Generation Women Leader’ for 2020, the best young investigator under the age of 40 by the International Menopause Society (‘Robert Greenblatt Award’), one of ten best UK young scientists in the biomedical sector by the UK Government ‘STEM for Britain’, and she is considered as one of 11 scientists with the highest impact on innovations in menopause by Forbes.