Reproductive Health

Our research in this area focusses largely on women's health and reproductive ageing across the life course. This covers aspects of fertility and reproductive behaviours, with a particular focus on ovarian biology and mechanisms. We also have specific interest in a number of reproductive disorders, including Polycystic Ovary Syndrome (PCOS) and Premature Ovarian Insufficiency (POI). Our collaborative work was the first to demonstrate that variation in DNA damage response is the key biological mechanism underpinning female ovarian ageing and fertility.

The papers highlighted below are selected from ~150 published research articles. I am starred first or last author on all papers unless otherwise stated, but all research was conducted in a multi-disciplinary, collaborative team environment across multiple institutions.

Selected publications

1 / Stankovic et al, ‘Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring’ Medrxiv (2022)

Largest ovarian ageing exome sequencing study to date, highlighting a number of novel genes where loss of function has a large effect on reproductive lifespan - notably ZNF518A which appears to be a key transcriptional regulator in oocytes. This study was also the first to demonstrate that female mutation rate is heritable, and that maternal predisposition to earlier ovarian ageing may influence de novo mutation rate and health outcomes in offspring. (link)

2 / Mathieson et al, ‘Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus’ medRxiv (2022)

Largest published GWAS on fertility and childlessness to date, highlighting the first example of a locus (FADS1/2) under both historical and modern day natural selection (link)

3 / Ruth et al, ‘Genetic insights into the biological mechanisms governing human ovarian ageing’ Nature (2021)

This paper demonstrated that genes highlighted by human genetics can be manipulated in animal models to extend reproductive health and enhance fertility. It also demonstrated that Premature Ovarian Insufficiency (POI) has a polygenic component and that earlier ovarian ageing is a causal risk factor for poor bone and metabolic health. (link)

4 / Pirastu et al, ‘Genetic analyses identify widespread sex-differential participation bias’ Nature Genetics (2021)

Not strictly related to reproductive biology, but the largest genetic study to date which highlights important sex-specific biases in population study participation. For example, women with higher genetic susceptibility to obesity are less likely to participate in studies than their male equivalents. (link)

5 / Ruth et al, ‘Using human genetics to understand the disease impacts of testosterone in men and women’
Nature Medicine (2020)

This project identified nearly all known genetic determinants of circulating testosterone to date. We use these genetics findings to demonstrate that increased testosterone levels are causally beneficial for male metabolic health (predicting the outcome of a subsequent clinical trial), but deleterious for women's metabolic health. (link)

6 / Ganna et al, ‘Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior’ Science (2019)

This study was the first to identify genetic variants reproducibly associated with sexual orientation. Importantly it demonstrates that sexuality is highly complex, with no simple continuum from opposite-sex to same-sex preference, reflecting natural variation underpinned by biological mechanisms. (link)

7 / Day et al, ‘Elucidating the genetic architecture of reproductive ageing in the Japanese population’
Nature Communications (2018)

First large-scale genetic study on reproductive lifespan conducted in women of non-European ancestry. Demonstrated an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in animal models. (link)

8 / Day et al, ‘Physical and neurobehavioral determinants of reproductive onset and success’ Nature Genetics (2016)

One of my favourite papers! This was one of the first genetics projects we did in UK Biobank, identifying some of the earliest genetic determinants of fertility and reproductive behaviour. Notably it also identified the first example of a genetic variant influencing a behavioural trait (risk tasking) at the CADM2 gene locus. (link)

9 / Day et al, 'Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome'. Nature Communications (2015)

One of the first collaborative projects we had with 23andMe, which was at the time the largest genetic discovery analysis for PCOS. This was the first paper demonstrating that whilst PCOS disease cases are phenotypically and clinically heterogenous, the underlying biology and genetic is not. This observation was key for enabling much larger future meta-analyses of different patient cohorts. (link)

10 / Day et al, 'Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair’ Nature Genetics (2015)

Building on findings from Stolk et al (see below), this paper demonstrated that variation in DNA damage response (DDR) was the major pathway governing ovarian ageing. It also demonstrated a causal association between ovarian ageing and hormone-sensitive cancers, and identified the first common variant in BRCA1 associated with a complex trait. (link)

11 / Stolk et al, 'Meta-analyses identify 13 loci associated with age at menopause and highlights DNA repair and immune pathways’ Nature Genetics (2012)

This was the first paper to suggest that DNA damage response (DDR) genes might contribute to population variation in ovarian ageing. (link)