Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study

Abstract

Women become infertile approximately 10 years before menopause, and as more women delay childbirth into their 30s, the number of women who experience infertility is likely to increase. Tests that predict the timing of menopause would allow women to make informed reproductive decisions. Current predictors are only effective just prior to menopause, and there are no long-range indicators. Age at menopause and early menopause (EM) are highly heritable, suggesting a genetic aetiology. Recent genome-wide scans have identified four loci associated with variation in the age of normal menopause (40-60 years). We aimed to determine whether theses loci are also risk factors for EM. We tested the four menopause-associated genetic variants in a cohort of approximately 2000 women with menopause≤45 years from the Breakthrough Generations Study (BGS). All four variants significantly increased the odds of having EM. Comparing the 4.5% of individuals with the lowest number of risk alleles (two or three) with the 3.0% with the highest number (eight risk alleles), the odds ratio was 4.1 (95% CI 2.4-7.1, P=4.0×10(-7)). In combination, the four variants discriminated EM cases with a receiver operator characteristic area under the curve of 0.6. Four common genetic variants identified by genome-wide association studies, had a significant impact on the odds of having EM in an independent cohort from the BGS. The discriminative power is still limited, but as more variants are discovered they may be useful for predicting reproductive lifespan.

Figure 1.

Number of EM risk alleles for all four SNPs in women with menopause at 45 and below (EM) compared with women who had menopause after the age of 45 years (controls).

Figure 2.

ORs of EM for each number of risk alleles compared with the median number of five risk alleles (indicated by a square). ORs are plotted as diamonds and 95% confidence intervals are indicated with vertical lines.

Figure 3.

ROC plot modelling the discriminatory power of all four menopause SNPs, for EM (≤45). On the y-axis is the true-positive rate or sensitivity of the test for predicting EM and on the x-axis is the false-positive rate or specificity of the SNPs for predicting EM.