Abstract
Menopause is the endpoint of a process referred to as ovarian ageing. The mean age at menopause is approximately 51 years, but varies widely between 40 to 60 years of age. Approximately 1% of all women experience menopause before the age of 40, which is a condition known as primary
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ovarian insufficiency (POI). Timing of menopause has great implications for female fertility and general health (e.g. osteoporosis and cardiovascular disease). Although the exact physiological processes underlying the timing of menopause are far from elucidated at present, genetic factors have proven to play a major role in determining this variation in menopausal age. The identification of genetic variants associated with (early) ovarian ageing and thereby infertility and consequences for health later in life, constitutes the core of this thesis. To identify genetic variants in timing of (early) menopause, four candidate gene association studies on single nucleotide polymorphisms (SNPs) and structural variants, a genome-wide association study (GWAS) and a gene-gene interaction analysis were conducted and are described in this thesis. In a candidate gene association study in five genes involved in primordial follicle recruitment conducted in 3616 postmenopausal women, the AMHR2 (in interaction with parity) and BMP15 gene were associated with timing of menopause. A subsequent gene-gene interaction analysis in these five genes identified an interaction between SNPs in the AMH and AMHR2 gene, suggesting a role of the AMH signaling pathway in the onset of natural menopause. The number of CGG repeats in the FMR1 gene in the premutation range (55-200 repeats) have been repeatedly associated with POI and account for approximately 1-8% of all cases of POI. It has been suggested that the number of FMR1 CGG repeats in the normal and intermediate range (up to 55 repeats) are also associated with (early) ovarian ageing. However, in a large population-based sample of 3611 postmenopausal women we found no association between the number of FMR1 CGG repeats and age at menopause. Also, in a case-control study of 375 women with idiopathic POI and 3368 controls with natural menopause above 40 years of age, no association was found between normal and intermediate ranged CGG repeats in the FMR1 gene and the risk of POI. Together, these results question the role of FMR1 CGG repeat sizes up to 55 repeats in the ovarian ageing process. In a GWAS conducted in a cohort of 901 European idiopathic POI and early menopause (EM) cases compared to 2209 controls with an age at natural menopause over 45 years, the strongest association was seen in a locus near the BRSK1 gene on chromosome 19. Interestingly, this locus was previously identified in GWAS in natural menopause above 40 years. This finding supports the evidence that POI, EM and normal menopause share at least a proportion of their genetic aetiology. Additionally, a number of potentially interesting specific loci for POI and EM were identified, including NELL1, PGCF5, MTM1 and MTMR1
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