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

Autoři: Jonathan M. Chernus aff001;  Emily G. Allen aff002;  Zhen Zeng aff003;  Eva R. Hoffman aff004;  Terry J. Hassold aff005;  Eleanor Feingold aff001;  Stephanie L. Sherman aff002
Působiště autorů: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America aff001;  Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America aff002;  Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America aff003;  Center for Chromosome Stability, University of Copenhagen, Copenhagen, Denmark aff004;  School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, Washington, United States of America aff005
Vyšlo v časopise: A candidate gene analysis and GWAS for genes associated with maternal nondisjunction of chromosome 21. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008414
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008414


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.

Klíčová slova:

Down syndrome – Genetic loci – Genome-wide association studies – Homologous recombination – Chromosome structure and function – Chromosomes – Meiosis – Oocytes


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