Scientists uncover rare genetic mutations that not only influence the timing of menopause but also heighten cancer risk, providing groundbreaking insights into the genetic factors shaping women’s reproductive health and longevity.
Study: Genetic links between ovarian ageing, cancer risk and de novo mutation rates. Image Credit: ClareM / Shutterstock
A recent study published in the journal Nature revealed new insights into the genetic links between de novo mutation (DNM) rates, ovarian aging, and cancer risk.
Female reproductive longevity varies substantially and profoundly affects health and fertility in later life. Females have a non-renewable ovarian reserve established during fetal development, which depletes continuously throughout the reproductive life, leading to menopause. Menopause timing varies based on the differences in the initial oocyte pool size and follicle loss rate.
Natural fertility is closely associated with the timing of menopause, decreasing as early as ten years before menopause. Genome-wide association studies (GWAS) have identified about 300 genomic loci associated with menopause timing. These variants explain up to 38% of single nucleotide polymorphism heritability and 12% of the variance in age at natural menopause (ANM).
Genetic studies on ANM have primarily centered on common genetic variation, with little focus on rare protein-coding variants. Previous whole-exome sequencing (WES) analyses have identified gene-based associations with ANM for ClpB family mitochondrial disaggregase (CLPB), checkpoint kinase 2 (CHEK2), BRCA2 DNA repair associated (BRCA2), DNA topoisomerase III alpha (TOP3A), DNA helicase B (HELB), and DNA cross-link repair 1A (DCLRE1A).
The study and findings
In this new study, researchers investigate the role of rare damaging variants in ovarian aging. They used WES data of 106,974 postmenopausal female participants in the United Kingdom (UK) Biobank and performed individual gene burden association tests. Rare exome variants were classified into three categories: 1) missense variants, 2) high-confidence protein-truncating variants (HC-PTVs), and 3) damaging variants (combination of HC-PTVs and missense variants).
The team identified rare variants in nine genes associated with ANM, three of which (BRCA2, HELB, and CHEK2) were reported in prior UK Biobank WES analyses. They corroborated the associations of CHEK2 and HELB with 1.57 and 1.84 years later ANM, respectively, and the previously borderline association of homologous recombination factor with OB-fold (HROB) with 2.89 years earlier ANM. Interestingly, carriers of BRCA2 HC-PTV were found to have 1.18 years earlier ANM.
Further, novel rare variants were identified in SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1), partner and localizer of BRCA2 (PALB2), patatin-like phospholipase domain containing 8 (PNPLA8), zinc finger protein 518A (ZNF518A), and ETAA1 activator of ATR kinase (ETAA1). The effect sizes ranged between 5.61 years earlier ANM for ZNF518A HC-PTV carriers and 1.35 years later ANM for SAMHD1 damaging variant carriers.
Next, the team integrated these exome-wide results with the largest common variant GWAS of ANM. Five of the nine ANM genes (CHEK2, HELB, ETAA1, ZNF518A, and BRCA2) were mapped within 500 kb of a common GWAS signal. Three non-coding common GWAS signals were proximal to ZNF518A. Further, the researchers showed that common ANM-associated variants were enriched in ZNF518A binding sites.
The largest GWAS for age at menarche revealed a common variant at ZNF518A for later puberty in females. Supporting this finding, the researchers observed that ZNF518A PTVs were also associated with later age at menarche. In addition, common variants related to puberty in females were enriched in transcriptional targets of ZNF518A.
Next, the researchers investigated the effects of genes associated with ANM on cancer outcomes. Their analysis consistently replicated reported associations between PTVs in PALB2, BRCA2, and CHEK2 and cancer outcomes. Further, a novel association was observed for HC-PTVs and SAMHD1 damaging variants with all cancers in both sexes. Notably, SAMHD1 alleles increasing cancer risk were associated with later ANM.
Finally, the team tested whether the genetic susceptibility to earlier ovarian aging increased the DNM rate in the offspring. As such, they analyzed parent-offspring trios from the 100,000 Genome Project and computed a polygenic score for ANM in the parents. They noted that the maternal genetic susceptibility to earlier ANM was linked to a higher rate of maternally derived DNMs in the offspring. However, this association was not replicated in an independent cohort, underscoring the need for further investigation.
Conclusions
Together, the study identified nine ANM genes, increasing the number of genes implicated in ovarian aging by identifying rare protein-coding variants. Effect sizes ranged from 5.61 years earlier to 1.35 years later ANM compared to the maximum effect size of 1.06 years reported for common variants. Deleterious variants in SAMHD1, CHEK2, and HELB were associated with increased ANM. Seven ANM genes are known to be involved in DNA damage repair.
Enrichment of GWAS signals at ZNF518A binding sites suggests that ZNF518A regulates genes related to reproductive longevity by repressing regulatory elements distal to the transcription initiation sites. Females carrying rare PTVs in ZNF518A have shorter reproductive lifespans due to delayed puberty and earlier menopause.
Damaging variants in SAMHD1 were associated with an increased all-cancer risk in males and females, hormone-sensitive cancers in females, and prostate cancer in males. While the team noted that maternal genetic susceptibility to earlier ANM was associated with a higher DNM rate in offspring, they caution that this association was not replicated in an independent cohort. Future large-scale studies will be necessary to explore this relationship further and confirm the findings..