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. 2019 Dec 12;15(12):e1008414.
doi: 10.1371/journal.pgen.1008414. eCollection 2019 Dec.

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

Jonathan M Chernus  1 , Emily G Allen  2 , Zhen Zeng  3 , Eva R Hoffman  4 , Terry J Hassold  5 , Eleanor Feingold  1   3 , Stephanie L Sherman  2
Affiliations

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

Jonathan M Chernus et al. PLoS Genet. .

Abstract

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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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. LocusZoom plot for RAD21L.
In this Figure (as in Figs 2–12) four LocusZoom plots show the results at one locus across all four analyses. Each point is one variant, with the x- and y-axes representing physical position on the chromosome and -log10(p-value), respectively. Open squares and asterisks represent genotyped and imputed variants, respectively. Coloring represents linkage disequilibrium (red = stronger, blue = weaker) with the tagging SNP (which is purple). The overlaid blue curve shows the recombination rate.
Fig 2
Fig 2. LocusZoom plot for SYCE2.
Fig 3
Fig 3. LocusZoom plot for SYCP1.
Fig 4
Fig 4. LocusZoom plot for SYCP2.
Fig 5
Fig 5. LocusZoom plot for SMEK1.
Fig 6
Fig 6. LocusZoom plot for VEGFA.
Fig 7
Fig 7. LocusZoom plot for SLC39A10.
Fig 8
Fig 8. LocusZoom plot for AURKC.
Fig 9
Fig 9. LocusZoom plot for rs9984132 on chromosome 21.
Fig 10
Fig 10. LocusZoom plot for DLGAP2.
Fig 11
Fig 11. LocusZoom plot for CPEB2.
Fig 12
Fig 12. LocusZoom plot for MYO10.
See this image and copyright information in PMC

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