Rare coding variants in DNA damage repair genes associated with timing of natural menopause

Ward, Lucas D.; Parker, Margaret M.; Deaton, Aimée M.; Tu, Ho-Chou; Flynn-Carroll, Alexander O.; Hinkle, Gregory; Nioi, Paul

doi:10.1016/j.xhgg.2021.100079

Cited by 8 publications

(20 citation statements)

References 61 publications

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“…We next sought to understand why previous analyses of UKBB WES data missed the associations we report here, and conversely why we did not identify associations with other previously reported genes. Of the seven genes identified by Ward et al 9 , three were also identified by our study (CHEK2, HELB and HROB), three were recovered when we increased our burden test MAF threshold from 0.1% to 1% (DCLRE1A, RAD54L, TOP3A), and an additional gene fell just below our P value threshold when considering variants with <1% MAF (CLPB; P =1.2*10 -5 ). In contrast, our discovery of novel associations that were not reported by Ward et al (BRCA2, ETAA1, PALB2, PNPLA8, SAMHD1 and ZNF518A) were likely explained by differences in phenotype preparation, sample size, variant annotation and the statistical model used (see Supplementary Note and Supplementary Table 3).…”

Section: Exome-wide Gene Burden Associations With Anmsupporting

confidence: 45%

“…These were confirmed by an independent group of analysts using different QC and analysis pipelines ( Supplementary Tables 1, 2 ). Three of these genes have been previously reported in UKBB WES analysis 9 - we confirm the associations of CHEK2 (beta=1.57 years, 95% CI: 1.23-1.92, P =1.60*10 -21 , N=578 damaging allele carriers) and HELB (beta=1.84, 95% CI: 1.08-2.60, P =4.20*10 -7 , N=120 HC-PTV carriers) with later ANM and a previously borderline association of HROB with earlier ANM (beta= -2.89 years, 95% CI: 1.86-3.92, P =1.90*10 -8 , N=65 HC-PTV carriers). In addition, our previous ANM GWAS analyses 1 identified an individual low-frequency PTV variant in BRCA2 , which we now extend to demonstrate that, in aggregate, BRCA2 HC-PTV carriers exhibit 1.18 years earlier ANM (beta= -1.18, 95% CI: 0.72-1.65, P =2.60*10 -7 , N=323).…”

Section: Resultsmentioning

confidence: 97%

“…The age at natural menopause results obtained via BOLT-LMM are available in Supplementary Table 1. Furthermore, in order to compare and explain potential differences between our WES results and the previously published one 9 , we ran the above described approach using MAF < 1%, a cutoff applied by Ward et…”

Section: Exome-wide Association Analyses In the Uk Biobankmentioning

confidence: 99%

“…Previous genome-wide association studies (GWAS) have successfully identified ∼300 distinct common genomic loci associated with the timing of menopause 1 . These reported variants cumulatively explain 10% - 12% of the variance in ANM and 31-38% of the overall estimated SNP heritability 1,9,10 . The majority of these loci implicate genes that regulate DNA damage response (DDR), highlighting the particular sensitivity of oocytes to DNA damage due to the prolonged state of cell cycle arrest across the life-course 1,7,11–20 .…”

Section: Introductionmentioning

confidence: 99%

“…Genetic studies for ANM to date have largely focussed on assessing common genetic variation, with little insight into the role of rarer, protein-coding variants. Initial exome-sequencing (WES) analyses in UK Biobank identified gene-based associations with ANM for CHEK2, DCLRE1A, HELB, TOP3A, BRCA2 and CLPB 1,9 . In this study, we aimed to explore the role of rare damaging variants in ovarian ageing in greater detail through a combination of enhanced phenotype curation, better powered statistical tests and assessment of different types of variant classes at lower allele frequency thresholds ( Supplementary Note ).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

Stankovic

Shekari

Huang

et al. 2022

Preprint

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Human genetic studies have provided substantial insight into the biological mechanisms governing ovarian ageing, yet previous approaches have been largely restricted to assessing common genetic variation. Here we report analyses of rare (MAF<0.1%) protein-coding variants in the exomes of 106,973 women from the UK Biobank study, implicating novel genes with effect sizes up to ~5 times larger than previously discovered in analyses of common variants. These include protein truncating variants in ZNF518A, which shorten reproductive lifespan by promoting both earlier age at natural menopause (ANM, 5.61 years [4.04-7.18], P=2*10-12) and later puberty timing in girls (age at menarche, 0.56 years [0.15-0.97], P=9.2*10-3). By integrating ChIP-Seq data, we demonstrate that common variants associated with ANM and menarche are enriched in the binding sites of ZNF518A. We also identify further links between ovarian ageing and cancer susceptibility, highlighting damaging germline variants in SAMHD1 that delay ANM and increase all-cause cancer risk in both males (OR=2.1 [1.7-2.6], P=4.7*10-13) and females (OR=1.61 [1.31-1.96], P=4*10-6). Finally, we demonstrate that genetic susceptibility to earlier ovarian ageing in women increases de novo mutation rate in their offspring. This provides direct evidence that female mutation rate is heritable and highlights an example of a mechanism for the maternal genome influencing child health.

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Section: Exome-wide Gene Burden Associations With Anmsupporting

confidence: 45%

Section: Resultsmentioning

confidence: 97%

Section: Exome-wide Association Analyses In the Uk Biobankmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

Stankovic

Shekari

Huang

et al. 2022

Preprint

View full text Add to dashboard Cite

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Genetic insights into the age-specific biological mechanisms governing human ovarian ageing

Ojavee

Darrous

Patxot

et al. 2023

Preprint

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There is currently little evidence that the genetic basis of human phenotype varies signifi- cantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect. Nineteen of these replicated discoveries are identified only by our modelling framework, which determines the time-dependency of DNA variant-age-at-onset associations, without a significant multiple-testing burden. Across the range of early to late menopause, we find evidence for significantly different underlying biological pathways, changes in the sign of genetic correlations of ANM to health indicators and outcomes, and differences in inferred causal relationships. We find that DNA damage response processes only act to shape ovarian reserve and depletion for women of early ANM. Genetically mediated delays in ANM were associated with increased relative risk of breast cancer and leiomyoma at all ages, and with high cholesterol and heart failure for late-ANM women. These findings suggest that a better understanding of the age-dependency of genetic risk factor relationships among health indicators and outcomes is achievable through appropriate statistical modelling of large-scale biobank data.

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Single-cell and bulk transcriptional profiling of mouse ovaries reveals novel genes and pathways associated with DNA damage response in oocytes

Mills,

Emori,

Kumar

et al. 2024

Preprint

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Immature oocytes enclosed in primordial follicles stored in female ovaries are under constant threat of DNA damage induced by endogenous and exogenous factors. Checkpoint kinase 2 (CHEK2) is a key mediator of the DNA damage response in all cells. Genetic studies have shown that CHEK2 and its downstream targets, p53 and TAp63, regulate primordial follicle elimination in response to DNA damage, however the mechanism leading to their demise is still poorly characterized. Single-cell and bulk RNA sequencing were used to determine the DNA damage response in wildtype and Chek2-deficient ovaries. A low but oocyte-lethal dose of ionizing radiation induces a DNA damage response in ovarian cells that is solely dependent on CHEK2. DNA damage activates multiple ovarian response pathways related to apoptosis, p53, interferon signaling, inflammation, cell adhesion, and intercellular communication. These pathways are differentially employed by different ovarian cell types, with oocytes disproportionately affected by radiation. Novel genes and pathways are induced by radiation specifically in oocytes, shedding light on their sensitivity to DNA damage, and implicating a coordinated response between oocytes and pre-granulosa cells within the follicle. These findings provide a foundation for future studies on the specific mechanisms regulating oocyte survival in the context of aging, as well as therapeutic and environmental genotoxic exposures.

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Rare coding variants in DNA damage repair genes associated with timing of natural menopause

Cited by 8 publications

References 61 publications

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

Genetic insights into the age-specific biological mechanisms governing human ovarian ageing

Single-cell and bulk transcriptional profiling of mouse ovaries reveals novel genes and pathways associated with DNA damage response in oocytes

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