A genome-wide association study of early menopause and the combined impact of identified variants

Abstract

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Figure 1.

Effect on normal age of menopause as a QT plotted against the odds of EM (<45 years) or POI (<40 years) for each of 17 ReproGen age at menopause GWAS SNPs.

Figure 2.

Distribution of the age at menopause-lowering allele score (quintiles) in women with EM and controls and ORs (95% CIs) for EM. Data shown are from the two replication cohorts combined. OR's are calculated relative to the median quintile.