| dc.description.abstract | The objective of my research was to investigate the rare and very-rare genetic factors influencing female reproductive ageing in humans using large-scale population exome-sequencing data. Over the past decade, most studies have relied on non-sequencing genomic data, which only allowed analysis of common genomic variants. However, these genome-wide array studies have limitations in capturing the complete range of genetic variation. Consequently, our understanding of the role of rare genomic variants, which may have a significant impact on menopause timing, has been limited. Furthermore, comprehensive studies exploring genetic factors associated with menopause age, particularly early and very early menopause, have been limited by the lack of large-scale sequencing genomic data, such as population-based datasets. Most of the previously published research has been derived from clinical and family studies, and there has been a dearth of population-based studies that can validate and identify novel genomic factors using a cohort of healthy individuals. Consequently, my aim was to utilise population whole-exome sequencing data for the first time to advance our understanding of genomic factors that impact female reproductive lifespan.
In Chapter 1, I provide an introduction to the biology of menopause. I emphasise the importance of studying menopause timing and the revolutionary impact of using population sequencing genomic data to improve our understanding of the underlying genomic causes of menopause timing.
Chapter 2 comprises analysis focusing on the correlation between bone morphogenetic protein 15 (BMP15) and its previously reported variants in relation to menopause timing. The BMP15 gene and its missense variants have been identified as a potential candidate for premature ovarian insufficiency (POI) based on prior investigations. However, our study revealed no evidence of the previously reported variants being causative factors for POI. Furthermore, when conducting a gene burden association test, we found no significant association between various types of BMP15 variants and early menopause.
Chapter 3 builds based on the previous chapter, which presents an in-depth analysis aimed at assessing the penetrance of over 100 genes associated with premature ovarian insufficiency (POI). The findings of this investigation provide limited evidence supporting the existence of autosomal dominant effects in the reported POI genes. Surprisingly, the vast majority of heterozygous effects on these genes were ruled out, with 99.9% of all protein-truncating variants being observed in women with normal reproductive health. However, we did observe evidence of haploinsufficiency effects in certain genes, including TWNK and SOHLH2.
Chapter 4 is an exome-wide association study to identify rare genetic variants associated with menopause timing. We identified effects ~5 times larger than previously discovered in analyses of common variants, highlighting protein-coding variants in ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1. We found rare loss-of-function variants in the ZNF518A gene, which reduced menopause age by approximately six years.
Chapter 5 culminates by assessing the significant contributions made by this study in advancing our comprehension of the variation in genetic risk factors associated with female reproductive lifespan. Additionally, it outlines potential directions for future research in this field, highlighting areas that warrant further exploration and investigation. | en_GB |
