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

Autor: Jonathan M. Chernus, Stephanie L. Sherman, Terry J. Hassold, Zhen Zeng, Eleanor Feingold, Emily G. Allen, Eva R. Hoffman
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
Vascular Endothelial Growth Factor A
Cancer Research
Candidate gene
Genome-wide association study
QH426-470
Biochemistry
Chromosomal Disorders
0302 clinical medicine
Nondisjunction
Genetic
Animal Cells
Medicine and Health Sciences
Aurora Kinase C
Cell Cycle and Cell Division
Homologous Recombination
Child
Cation Transport Proteins
Genetics (clinical)
Genetics
0303 health sciences
Chromosome Biology
Genomics
Nucleic acids
Meiosis
Nondisjunction
Cell Processes
OVA
Female
Cellular Types
Candidate Gene Analysis
Research Article
Chromosome Structure and Function
DNA recombination
Mothers
Biology
Chromosomes
03 medical and health sciences
Genome-Wide Association Studies
medicine
Humans
Genetic Predisposition to Disease
Molecular Biology
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Clinical Genetics
Meiosis II
Biology and Life Sciences
Computational Biology
Human Genetics
Cell Biology
DNA
Genome Analysis
medicine.disease
United States
Germ Cells
Genetic Loci
Oocytes
Down Syndrome
Chromosome 21
Trisomy
030217 neurology & neurosurgery
Genome-Wide Association Study
Zdroj: PLoS Genetics, Vol 15, Iss 12, p e1008414 (2019)
Chernus, J M, Allen, E G, Zeng, Z, Hoffman, E R, Hassold, T J, Feingold, E & Sherman, S L 2019, ' A candidate gene analysis and GWAS for genes associated with maternal nondisjunction of chromosome 21 ', PLOS Genetics, vol. 15, no. 12, e1008414 . https://doi.org/10.1371/journal.pgen.1008414
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: 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.
Author summary Approximately one of every 700 babies is born with trisomy 21—an extra copy of chromosome 21. Trisomy 21 is caused by the failure of chromosomes to segregate properly during meiosis, generally in the mother. Past studies have defined altered patterns of recombination along nondisjoined chromosomes as risk factors for human nondisjunction and model systems have clearly shown that specific genes involved recombination and other early meiotic processes play a role in the fidelity of chromosome segregation. However, no genome-wide genetic study (GWAS) has ever been conducted using maternal human nondisjunction as the disease phenotype. This study takes the first step to understand predisposing factors. We used chromosome 21 genotypes from the parents and child to identify mothers with nondisjunction errors derived in the oocyte and to establish the type of error (meiosis I or meiosis II). We then conducted a unique set of subgroup comparisons designed to leverage our previous work that shows that the etiologies of meiosis I and meiosis II nondisjunction differ for trisomy 21. Both the candidate gene study and the GWAS provide evidence that meiotic-specific structures and processes are vulnerable to genetic variants that lead to increased risk of human chromosome nondisjunction.
Databáze: OpenAIRE
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