Length of FMR1 repeat alleles within the normal range does not substantially affect the risk of early menopause.
Is the length of FMR1 repeat alleles within the normal range associated with the risk of early menopause?



The length of repeat alleles within the normal range does not substantially affect risk of early menopause.



There is a strong, well-established relationship between length of premutation FMR1 alleles and age at menopause, suggesting that this relationship could continue into the normal range. Within the normal range, there is conflicting evidence; differences in ovarian reserve have been identified with FMR1 repeat allele length, but a recent population-based study did not find any association with age at menopause as a quantitative trait.



We analysed cross-sectional baseline survey data collected at recruitment from 2004 to 2010 from a population-based, prospective epidemiological cohort study of >110 000 women to investigate whether repeat allele length was associated with early menopause.



We included 4333 women from the Breakthrough Generations Study (BGS), of whom 2118 were early menopause cases (menopause under 46 years) and 2215 were controls. We analysed the relationship between length of FMR1 alleles and early menopause using logistic regression with allele length as continuous and categorical variables. We also conducted analyses with the outcome age at menopause as a quantitative trait as well as appropriate sensitivity and exploratory analyses.



There was no association of the shorter or longer FMR1 allele or their combined genotype with the clinically relevant end point of early menopause in our main analysis. Likewise, there were no associations with age at menopause as a quantitative trait in our secondary analysis.



Women with homozygous alleles in the normal range may have undetected FMR1 premutation alleles, although there was no evidence to suggest this. We estimate minor dilution of risk of early menopause from the likely inclusion of some women with menopause at over 45 years in the early menopause cases due to age-rounding bias in self-reports.



There is no robust evidence in this large study that variation within the normal range of FMR1 repeat alleles influences timing of menopause in the general population, which contradicts findings from some earlier, mainly smaller studies. The FMR1 CGG repeat polymorphism in the normal range is unlikely to contribute to genetic susceptibility to early menopause.



We thank Breast Cancer Now and The Institute of Cancer Research for funding the BGS. The Institute of Cancer Research acknowledges NHS funding to the NIHR Biomedical Research Centre. The study was funded by the Wellcome Trust (grant number 085943). There are no competing interests.



Not applicable.
Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
Katherine S
KS
Ruth
Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
Claire E
CE
Bennett
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Minouk J
MJ
Schoemaker
Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
Michael N
MN
Weedon
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
Anthony J
AJ
Swerdlow
Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK A.Murray@exeter.ac.uk.
Anna
A
Murray
D000328:Adult; D000483:Alleles; D003430:Cross-Sectional Studies; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008593:Menopause / Q000235:genetics*; D008594:Menopause, Premature / Q000235:genetics*; D008875:Middle Aged; D018911:Trinucleotide Repeats
D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human
FMR1 protein; FMR1-related primary ovarian insufficiency; Fragile X-associated primary ovarian insufficiency; MeSH; human; menopause; premature menopause