Maternal Age and Oocyte Aneuploidy: Lessons Learned from Trisomy 21

Sherman, Stephanie L.; Allen, Emily G.; Bean, Lora Jh

doi:10.1007/978-1-4614-7187-5_6

Cited by 4 publications

(6 citation statements)

References 96 publications

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“…At least 5% and possibly as many as 20% of human conceptions are aneuploid as a result of errors in meiosis, and the vast majority of these errors occur in maternal meiosis I (MI), which begins in oocytes during fetal development and is arrested in prophase I for years until resumption in adulthood 1–5 . The decades‐long timespan for female meiosis and the different timescales and processes involved in completion of MI and meiosis II (MII) make maternal age a critical risk factor for nondisjunction but also make each stage susceptible to different error mechanisms 5,6 . In addition to maternal age, altered patterns of meiotic recombination are also associated with nondisjunction 7–13 .…”

Section: Introductionmentioning

confidence: 99%

“…In addition to maternal age, altered patterns of meiotic recombination are also associated with nondisjunction 7–13 . As one of the few aneuploid conditions with which humans survive to term, trisomy 21 provides crucial insight into human meiotic nondisjunction 6,14–16 …”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5] The decades-long timespan for female meiosis and the different timescales and processes involved in completion of MI and meiosis II (MII) make maternal age a critical risk factor for nondisjunction but also make each stage susceptible to different error mechanisms. 5,6 In addition to maternal age, altered patterns of meiotic recombination are also associated with nondisjunction. [7][8][9][10][11][12][13] As one of the few aneuploid conditions with which humans survive to term, trisomy 21 provides crucial insight into human meiotic nondisjunction.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10][11][12][13] As one of the few aneuploid conditions with which humans survive to term, trisomy 21 provides crucial insight into human meiotic nondisjunction. 6,[14][15][16] In our previous work, we performed the first genome-wide association study to find genetic risk factors for maternal nondisjunction of chromosome 21. 17 There we contrasted groups of mothers of live-born children with standard trisomy 21 derived from maternal nondisjunction with fathers (a convenient control group).…”

Section: Introductionmentioning

confidence: 99%

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Analyses stratified by maternal age and recombination further characterize genes associated with maternal nondisjunction of chromosome 21

2021

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Objective In our previous work, we performed the first genome‐wide association study to find genetic risk factors for maternal nondisjunction of chromosome 21. The objective of the current work was to perform stratified analyses of the same dataset to further elucidate potential mechanisms of genetic risk factors. Methods We focused on loci that were statistically significantly associated with maternal nondisjunction based on this same dataset in our previous study and performed stratified association analyses in seven subgroups defined by age and meiotic recombination profile. In each analysis, we contrasted a different subgroup of mothers with the same set of fathers, the mothers serving as cases (phenotype: meiotic nondisjunction of chromosome 21) and the fathers as controls. Results Our stratified analyses identified several genes whose patterns of association are consistent with generalized effects across groups, as well as other genes that are consistent with specific effects in certain groups. Conclusions While our results are epidemiological in nature and cannot conclusively prove mechanisms, we identified a number of patterns that are consistent with specific mechanisms. In many cases those mechanisms are strongly supported by available literature on the associated genes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analyses stratified by maternal age and recombination further characterize genes associated with maternal nondisjunction of chromosome 21

2021

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“…Thus, meiosis in females extends over a 10 to 50 year period; the age of the woman at conception reflects the age of the oocyte, and basically the period of arrest in MI. Given the mechanistic differences and temporal separation of maternal MI and MII, it is not surprising that associated risk factors differ for MI and MII nondisjunction errors (reviewed in [5]).…”

Section: Introductionmentioning

confidence: 99%

A candidate gene analysis and GWAS for genes associated with maternal nondisjunction of chromosome 21

et al. 2019

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Human nondisjunction errors in oocytes are the leading cause of pregnancy loss, and for pregnancies that continue to term, the leading cause of intellectual disabilities and birth defects. For the first time, we have conducted a candidate gene and genome-wide association study to identify genes associated with maternal nondisjunction of chromosome 21 as a first step to understand predisposing factors. A total of 2,186 study participants were genotyped on the HumanOmniExpressExome-8v1-2 array. These participants included 749 live birth offspring with standard trisomy 21 and 1,437 parents. Genotypes from the parents and child were then used to identify mothers with nondisjunction errors derived in the oocyte and to establish the type of error (meiosis I or meiosis II). We performed a unique set of subgroup comparisons designed to leverage our previous work suggesting that the etiologies of meiosis I and meiosis II nondisjunction differ for trisomy 21. For the candidate gene analysis, we selected genes associated with chromosome dynamics early in meiosis and genes associated with human global recombination counts. Several candidate genes showed strong associations with maternal nondisjunction of chromosome 21, demonstrating that genetic variants associated with normal variation in meiotic processes can be risk factors for nondisjunction. The genome-wide analysis also suggested several new potentially associated loci, although follow-up studies using independent samples are required.

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