title: Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health.
abstract: OBJECTIVE
  How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health?
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  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.
  
  
  RESULTS
  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 × 10(-16)], later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P = 5.7 × 10(-3)), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02-1.11; P = 4.8 × 10(-3)] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69-0.90; P = 4.1 × 10(-4)). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P < 5 × 10(-9)).
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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 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.
  
  
  BACKGROUND
  None.
  
  
  BACKGROUND
  Not applicable.
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Ruth
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Robin N
authors.initials: RN
authors.lastname: Beaumont
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tyrrell
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Jones
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Tuke
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wood
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK a.murray@exeter.ac.uk.
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
mesh_terms: D000328:Adult; D000368:Aged; D004715:Endometriosis / Q000235:genetics; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood* / Q000235:genetics; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics*; D056726:Genetic Association Studies; D005819:Genetic Markers; D006801:Humans; D007247:Infertility, Female / Q000235:genetics; D016014:Linear Models; D008297:Male; D008593:Menopause / Q000235:genetics*; D008597:Menstrual Cycle / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D060728:Reproductive Health
chemical_list: D037201:Follicle Stimulating Hormone, beta Subunit; D005819:Genetic Markers; D005640:Follicle Stimulating Hormone
keywords: FSH β subunit; endometriosis; fertility; menopause; menstrual cycle