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

Jonathan M Chernus,Eva R Hoffman,Terry J Hassold,Zhen Zeng,Stephanie L Sherman,Eleanor Feingold,Emily G Allen,R Scott Hawley

doi:10.1371/journal.pgen.1008414

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.

Highlights

Correct segregation of chromosomes during the two successive meiotic divisions is essential for the formation of haploid gametes
Homologs separate at the end of meiosis I (MI), whereas sister chromatids separate in meiosis II (MII)
We focused on candidate genes that have been associated with chromosome dynamics early in meiosis

Summary

Introduction

Correct segregation of chromosomes during the two successive meiotic divisions is essential for the formation of haploid gametes. At least 10% of human pregnancies produce aneuploid embryos with too many or too few chromosomes, the majority of which are lost during pregnancy. If they survive to term, many have severe congenital defects and developmental and intellectual disability. Meiosis in females is highly prone to chromosome segregation errors [i.e., nondisjunction or premature separation of sister chromatids (PSSC)] and these errors increase exponentially with increasing maternal age. In both sexes, meiosis starts with an initial step of DNA replication and the establishment of sister chromatid cohesion, followed by synapsis and recombination between homologous chromosomes. 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])

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