University of Bristol

Academic Institute

Kimberley BurrowsDr. Gemma FordAlex Shattock

B3784

The menopause is a significant event in the life of any woman, marking the end of their reproductive life. However, the timing of the menopause is not only associated with the end of fertility, but also the increased risk of mortality and developing serious morbidity, including cardiovascular disease; osteoporosis; and breast and endometrial cancer (Carty et al., 2013). Previous studies have concluded that the heritability of the age at natural menopause (ANM) is approximately 30-90% (Murabito, Yang, Fox and Cupples, 2005; Murabito, Yang, Fox, Wilson, et al., 2005; Long et al., 2006); therefore, understanding the precise pathways, genes and individual polymorphisms that affect the ANM, and therefore the risk of developing menopause-related disease, is important. The DNA damage response (DDR) pathway, and many genes within it, has been identified in several genome-wide association studies as significantly linked to the timing of the menopause (Stolk et al., 2012; Chen et al., 2014; Day et al., 2015; Wang et al., 2019). The mechanism behind this is theorised to be an increased rate of follicular atresia due to accumulating DNA damage, leading to earlier menopause in women with mutations that reduce the efficiency of genes within the DDR pathway (Stolk et al., 2012; Titus et al., 2013; Perry et al., 2014; Day et al., 2015). Menarche is another reproductive milestone within a woman’s life, and the age at menarche (AAM) could theoretically influence the ANM (Parazzini, 2007). The duration of the reproductive years - between the AAM and ANM – is associated with oestrogen exposure which can increase or reduce the risks of developing certain diseases, such as atherosclerosis (Cui et al., 2006).

The impact of individual SNPs within these genes on the ANM has been estimated by previous studies to be quite sizable, with the potential to alter the timing of menopause by more than 5 years. This would have a large impact on women’s risk of menopause-related disease. It is also important to understand the effect of SNPs with smaller effects that may still contribute to a large additive effect. There is conflict in the literature regarding the size of effect, significance and even the direction of effect of certain SNPs on the ANM and AAM. This project will help to understand the results of previous genome-wide association studies (GWAS’s), as well as potentially uncovering new associations in a smaller-scale association study. Although this MSc project is unlikely to result in a publication, it has the potential to be presented at a conference that would spread awareness of ALSPAC to a wider audience. In addition, results may inform additional projects furthering the collaboration between THS and PHS.

17/05/2021