Abstract
In recent years, common genetic variants have been identified by genome-wide association
studies (GWASs) that have led to the detection of 44 genetic loci associated with
approximately 6% of common variation in age at natural menopause. In the latest GWAS,
doubling the sample size to approximately 70,000 women more than doubled the number
of signals identified, from 17 to 56. In addition, low-frequency coding variants (<
5% minor allele frequency), with relatively large effect sizes, have been identified
in two genes, by analyzing genome-wide exome data. GWAS has been very successful in
identifying novel biological pathways involved in reproductive aging. Approximately
two-thirds of the loci reported so far include genes involved in DNA damage response
(DDR), highlighting the importance of this pathway in determining oocyte reserve.
In addition, GWAS demonstrates that the hypothalamic–pituitary axis is involved in
menopause timing as well as puberty timing, showing the first genetic link between
timing of the start and end of reproductive life. Genetic variants have been used
to explore the causal relationships between menopause timing and breast cancer. These
studies demonstrate that for a 1 year increase in menopause age, there is a 6% increase
in breast cancer risk, a value approximately double the estimate from epidemiological
studies. Prolonged exposure to estrogen during reproductive life is the likely mechanism,
rather than a direct effect of DDR variants on cancer risk. Further work is needed
to determine the mechanism for the effect of each variant identified by GWAS and more
variants will undoubtedly be discovered as sample sizes increase, denser single nucleotide
polymorphism arrays and reference genomes are used, and populations from diverse ethnic
groups are studied.
Keywords
menopause - GWAS - genetics - heritability - DNA damage response - breast cancer
