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).

In this project, we aim to investigate the associations between single nucleotide polymorphisms (SNPs) within genes of the DDR pathway and the ANM and AAM in mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC). This will form part of the research project component of my MSc degree in Reproduction and Development at the University of Bristol.
This proposal forms the basis of a multidisciplinary, collaborative MSc student research project which is being jointly supervised by research groups in Population Health Sciences and Translational Health Sciences, and financially supported by the MSc in Reproduction and Development within the Bristol Medical School. As part of this postgraduate taught MSc (https://www.bristol.ac.uk/study/postgraduate/2021/health-sciences/msc-re...), the 60-credit research project encompasses a student-led topic of interest, composed of a detailed literature review and a novel research dissertation which can be in the form of a data analysis project (this proposal) or a paper-based project.
As such, data extraction will be performed by an ALSPAC direct user (Kimberley Burrows) and this dataset will be sent to the ALSPAC data team for ID recoding prior to forwarding on to the primary analyst (Alex Shattock, RED MSc student 2020-21).

References
Carty, C. L., Spencer, K. L., Setiawan, V. W., et al. (2013) ‘Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.’, Human reproduction (Oxford, England), 28(6), pp. 1695–1706.
Chen, C. T. L., Liu, C.-T., Chen, G. K., et al. (2014) ‘Meta-analysis of loci associated with age at natural menopause in African-American women.’, Human molecular genetics, 23(12), pp. 3327–3342.
Day, F. R., Ruth, K. S., Thompson, D. J., et al. (2015) ‘Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.’, Nature genetics, 47(11), pp. 1294–1303.
Cui, R., Iso, H., Toyoshima, H., et al. (2006) ‘Relationships of age at menarche and menopause, and reproductive year with mortality from cardiovascular disease in Japanese postmenopausal women: the JACC study.’, Journal of epidemiology, 16(5), pp. 177–184.
Long, J.-R., Shu, X.-O., Cai, Q., et al. (2006) ‘Polymorphisms of the CYP1B1 gene may be associated with the onset of natural menopause in Chinese women.’, Maturitas, 55(3), pp. 238–246.
Murabito, J. M., Yang, Q., Fox, C. S. and Cupples, L. A. (2005) ‘Genome-wide linkage analysis to age at natural menopause in a community-based sample: the Framingham Heart Study.’, Fertility and sterility, 84(6), pp. 1674–1679.
Murabito, J. M., Yang, Q., Fox, C. S., Wilson, P. W. F., et al. (2005) ‘Heritability of age at natural menopause in the Framingham Heart Study.’, The Journal of clinical endocrinology and metabolism, 90(6), pp. 3427–3430.
Parazzini, F. (2007) ‘Determinants of age at menopause in women attending menopause clinics in Italy’, Maturitas, 56(3), pp. 280–287.
Perry, J. R. B., Hsu, Y.-H., Chasman, D. I., et al. (2014) ‘DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.’, Human molecular genetics, 23(9), pp. 2490–2497.
Stolk, L., Perry, J. R. B., Chasman, D. I., et al. (2012) ‘Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.’, Nature genetics, 44(3), pp. 260–268.
Titus, S., Li, F., Stobezki, R., et al. (2013) ‘Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans’, Science translational medicine, 5(172), p. 172ra21.
Wang, G., Lv, J., Qiu, X. and An, Y. (2019) ‘Integrating genome-wide association and eQTLs studies identifies the genes associated with age at menarche and age at natural menopause.’, PloS one, 14(6), p. e0213953.