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GWAS Links DNA Damage Response Genes to Age at Menopause

NEW YORK (GenomeWeb) – In an analysis of nearly 70,000 women, researchers from the University of Cambridge and elsewhere have linked more than 40 regions of the genome to a woman's age at menopause.

Many of these regions are associated with DNA damage response genes, including BRCA1, as the researchers reported today in Nature Genetics.

"We have known for some time that the age at which women go through menopause is partly determined by genes. This study now tells us that there are likely hundreds of genes involved, each altering menopause age by anything from a few weeks to a year," study author John Perry from Cambridge said in a statement. "It is striking that genes involved in DNA repair have such an important influence on the age of menopause, which we think is due to their effect on how quickly a woman's eggs are lost throughout her lifetime."

Women typically go through menopause between the ages of 40 years and 60 years of age, and earlier menopause has been linked to a lower risk of breast cancer, but a higher risk of osteoporosis, cardiovascular disease, and type 2 diabetes.

Through a genome-wide association study drawing on 69,360 women of European ancestry, Perry and his colleagues homed in on 1,208 SNPs that were significantly associated with age at natural menopause. Based on these SNPs, the researchers uncovered 54 independent signals in 44 genomic regions.

They then supplemented their GWAS with a meta-analysis of 39,026 women who'd been genotyped on exome arrays, and with a follow-up study of 10 low-frequency non-synonymous SNPs in 10,157 women from a Decode study that imputed rare variant genotypes. The combined analysis uncovered missense alleles in the HELB and SLCO4A1 genes that were linked to age at menopause.

HELB encodes DNA helicase B, a DNA helicase that unwinds DNA during replication, transcription, repair, and recombination, while SLCO4A1, or solute carrier organic anion transporter family, member 4A1, transports organic anions like thyroid hormones and estrone-3-sulfate, the researchers noted.

Perry and his colleagues' analyses also pointed to the contribution of other SNPs in DNA damage response pathways to age at menopause. Pathway analysis, they noted, found that 29 of the 44 regions highlighted by their GWAS contained one or more DNA damage response genes within 500 kilobases.

Intriguingly, the researchers uncovered a SNP signal that was highly correlated with four common nonsynonymous variants in BRCA1. None of those variants, the researchers noted, have been linked to breast cancer susceptibility. Additionally, 15 other signal genes, including, BRE, CHEK2, and RAD5, were found to have at least one direct link to BRCA1, such as being a binding partner.

Though many of the genes that Perry and his colleagues identified have roles in double-stranded break repair, they noted that genes in other repair mechanisms like mismatch repair and base-excision repair, as well as in DNA damage checkpoints and the cellular response to damage, were also linked to age at menopause.

Across the 56 SNPs linked to age at menopause, the researchers uncovered, using a Mendelian randomization approach, a positive correlation between the effect sizes in age at menopause and the effect size for breast cancer risk.

Using those SNPs, the researchers developed a polygenic risk score, which they weighted based on effect size of those SNPs. From that, they found that for each genetically predicted one-year increase in age at menopause, there was an associated 6 percent increase in risk of developing breast cancer.

Through that and additional stratified analyses, the researchers suggested that the menopause-related variants influence breast cancer risk by their influence on menopause timing.

The researchers further hypothesized that the DNA damage response, particularly double-stranded break repair, during recombination at meiosis may be a mechanism through which oocyte numbers are regulated. This then affects the size of the oocyte pool and the age at which menopause occurs.

"Many women today are choosing to have babies later in life, but they may find it difficult to conceive naturally because fertility starts to diminish at least 10 years before menopause," added senior author Anna Murray from the University of Exeter Medical School. "Our research has substantially increased our understanding of how reproductive aging in women happens, which we hope will lead to the development of new treatments to avoid early menopause."