Age at natural menopause is not linked with the follicle-stimulating hormone receptor region: a sib-pair study

Abstract

Objective Studies have shown that age at natural menopause is heritable. Mutations in the FSH-receptor have been identified in women with premature ovarian failure (POF) and the FSH-receptor gene may, therefore, be considered a candidate gene for (early) menopausal age. This study investigates whether there is linkage between genetic markers in the FSH-receptor region and (early) age at menopause using a sib-pair design. Design Sib-pair based linkage analysis. Setting Sister pairs and their first-degree family members from The Netherlands. Patient(s) The inclusion criteria for a family were natural menopause in upper or lower tail of the distribution of menopausal age in at least two sisters. A total of 126 families with at least one sib-pair were included in this study. Six polymorphic markers encompassing the FSH-receptor gene were genotyped. Intervention(s) None. Main outcome measure(s) Single point and multipoint logarithm of the odds (LOD) scores. Result(s) None of the markers showed evidence in favor of linkage with overall age at natural menopause or early age at natural menopause. Conclusion(s) Possibly, age at natural menopause in the more or less normal range is not part of the spectrum of phenotypes determined by mutations in the FSH-receptor gene. Alternatively, our results might be explained by genetic heterogeneity in the left tail of the distribution of menopausal age. This can limit the chance of finding a genetic locus, especially if this factor has a modest contribution to the phenotype.