study question: How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health?
summaryanswer: The T allele of the FSHB promoter polymorphism (rs10835638; c.-211G.T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis.
what is known already: The FSHB promoter polymorphism (rs10835638; c.-211G.T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS). study design, size, duration: We used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome-wide association study (GWAS) for length of menstrual cycle.
participants/materials, setting, methods: We included white British individuals aged 40 69 years in 2006 2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G.T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle.
main results and the role of chance: The FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12 0.20; P 6 10216], later age at menopause (0.13 years per minor allele; 95% CI 0.04 0.22; P 5.7 1023), greater female nulliparity [odds ratio (OR) 1.06; 95% CI 1.02 1.11; P 4.8 1023] and lower risk of endometriosis (OR 0.79; 95% CI 0.69 0.90; P 4.1 1024). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study andwe did not replicate associations with male infertility or PCOS. In theGWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P , 5 1029).
limitations, reasons for caution: The data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as irregular ). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect.
wider implications of the findings:We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and & The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Human Reproduction, Vol.31, No.2 pp. 473 481, 2016 Advanced Access publication on January 4, 2016 doi:10.1093/humrep/dev318 Downloaded from https://academic.oup.com/humrep/article-abstract/31/2/473/2380224 by University of Oxford - Bodleian Library user on 18 April 2018 endometriosis risk. These findings should now be verified in a second independent group of patients.We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS.
Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health
We aim to shed light on the processes which govern female reproduction throughout life. Female reproductive life begins at puberty when women start menstruating and ends at menopause when a woman?s supply of eggs becomes exhausted. On average most women start menstruating at about 13 years old, a process called menarche and go through menopause at about 50 years. Both of these processes are controlled jointly by genes and environmental factors. To date we have only identified a small proportion of the genetic influences and the environmental factors are not well understood. The length of reproductive lifespan impacts many aspects of female health, particularly fertility, breast cancer risk and osteoporosis. We aim to better understand the factors governing timing of menarche and menopause. In addition we will investigate the interaction of menopause risk factors and their impact on common diseases that have been linked to age at menopause, eg. heart disease and cancer. The study requires access to data only from female participants. We intend to make a subsequent linked application for access to genetic data when available. The long term impact of a better understanding of the processes that determine ovarian development and function may well lead to new methods of contraception, assisted fertility and fertility preservation.
|Lead investigator:||Anna Murray|
|Lead institution:||University of Exeter|