Certain rare variants have around five times larger effects on menopause timing than do previously identified common variants. Those rare variants included ETAA1, ZNF518A, PNPLA8, PALB2, and SAMHD1. A British research team mined UK BioBank data for this study, which appeared in Nature. Further, they found that damaging germline variants of SAMHD1 were associated with both extended reproductive lifespan and increased all-cause cancer risk in both men and women.
Protein-truncating variants in ZNF518A, they also found, are associated with shorter reproductive lifespan—that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). In addition, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), they showed that common genetic variants associated with earlier ovarian aging associate with an increased rate of maternally derived de novo mutations.
The study used Whole Exome Sequencing data available from 106,973 post-menopausal female UK Biobank participants of European genetic ancestry. The team conducted individual gene burden association tests by collapsing genetic variants according to their predicted functional categories. We defined three categories of rare exome variants with minor allele frequency (MAF) < 0.1%: high-confidence protein-truncating variants (HC-PTVs), missense variants with combined annotation-dependent depletion (CADD) score ≥ 25, and “damaging” variants (DMG, defined as combination of HC-PTVs and missense variants with CADD ≥ 25). “We analyzed 17,475 protein-coding genes with a minimum of 10 rare allele carriers in at least one of the masks tested,” the authors noted.
The timing of menopause affects fertility, and about 300 genomic loci associated with menopause timing have been identified through genome-wide association studies (GWAS). For example, GWAS analyses in the UK Biobank identified gene-based associations with ANM for CHEK2, DCLRE1A, HELB, TOP3A, BRCA2 and CLPB. So far, such variants explain up to 38% of single nucleotide polymorphism heritability and 12% of the variance in age at natural menopause (ANM).
Reproductive longevity in women varies substantially in the general population and has profound effects on fertility and health outcomes in later life. Women are born with a non-renewable ovarian reserve, which is established during fetal development. This reserve is continuously depleted throughout reproductive life, ultimately leading to menopause.
Variation in menopause timing is largely dependent on the differences in the size of the initial oocyte pool and the rate of follicle loss. Natural fertility is believed to be closely associated with menopause timing, and it declines on average ten years before the onset of menopause.
The effect of early menopause on infertility is becoming increasingly relevant as more people delay parenthood to later maternal age, especially in Western countries. In addition, normal variation in reproductive lifespan is associated with risk of a wide range of diseases, including type 2 diabetes mellitus, cancer, and osteoporosis.
The variation in timing of menopause reflects a complex mix of genetic and environmental factors that population-based studies have begun to unravel. Two-thirds of the GWAS signals detected so far, in research on menopause, implicate genes that regulate DNA damage response, highlighting the particular sensitivity of oocytes to DNA damage due to the prolonged state of cell cycle arrest across the lifetime.
