Identifying risk variants for embryo aneuploidy using ultra-low coverage whole-genome sequencing from preimplantation genetic testing

Siqi Sun; Mansour Aboelenain; Daniel Ariad; Mary E Haywood; Charles R Wageman; Marlena Duke; Aishee Bag; Manuel Viotti; Mandy Katz-Jaffe; Rajiv C McCoy; Karen Schindler; Jinchuan Xing

doi:10.1016/j.ajhg.2023.11.002

Identifying risk variants for embryo aneuploidy using ultra-low coverage whole-genome sequencing from preimplantation genetic testing

Am J Hum Genet. 2023 Dec 7;110(12):2092-2102. doi: 10.1016/j.ajhg.2023.11.002. Epub 2023 Nov 28.

Authors

Affiliations

¹ Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
² Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA; Department of Theriogenology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt.
³ Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
⁴ CCRM Genetics, Lone Tree, CO, USA.
⁵ Zouves Foundation for Reproductive Medicine, Foster City, CA, USA; Kindlabs, Kindbody, New York, NY, USA.
⁶ Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA; Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
⁷ Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA; Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. Electronic address: jinchuan.xing@rutgers.edu.

PMID: 38029743
PMCID: PMC10716496 (available on 2024-06-07)
DOI: 10.1016/j.ajhg.2023.11.002

Abstract

Aneuploidy frequently arises during human meiosis and is the primary cause of early miscarriage and in vitro fertilization (IVF) failure. Individuals undergoing IVF exhibit significant variability in aneuploidy rates, although the exact genetic causes of the variability in aneuploid egg production remain unclear. Preimplantation genetic testing for aneuploidy (PGT-A) using next-generation sequencing is a standard test for identifying and selecting IVF-derived euploid embryos. The wealth of embryo aneuploidy data and ultra-low coverage whole-genome sequencing (ulc-WGS) data from PGT-A have the potential to discover variants in parental genomes that are associated with aneuploidy risk in their embryos. Using ulc-WGS data from ∼10,000 PGT-A biopsies, we imputed genotype likelihoods of genetic variants in embryo genomes. We then used the imputed variants and embryo aneuploidy calls to perform a genome-wide association study of aneuploidy incidence. Finally, we carried out functional evaluation of the identified candidate gene in a mouse oocyte system. We identified one locus on chromosome 3 that is significantly associated with meiotic aneuploidy risk. One candidate gene, CCDC66, encompassed by this locus, is involved in chromosome segregation during meiosis. Using mouse oocytes, we showed that CCDC66 regulates meiotic progression and chromosome segregation fidelity, especially in older mice. Our work extended the research utility of PGT-A ulc-WGS data by allowing robust association testing and improved the understanding of the genetic contribution to maternal meiotic aneuploidy risk. Importantly, we introduce a generalizable method that has potential to be leveraged for similar association studies that use ulc-WGS data.

Keywords: CCDC66; embryo aneuploidy; genome-wide association study; preimplantation genetic testing for aneuploidy; ultra-low-coverage whole-genome sequencing.

MeSH terms

Aneuploidy
Animals
Blastocyst
Eye Proteins
Female
Fertilization in Vitro
Genetic Testing / methods
Genome-Wide Association Study
Humans
Mice
Pregnancy
Preimplantation Diagnosis* / methods

Substances

CCDC66 protein, human
Eye Proteins

Abstract

MeSH terms

Substances

Grants and funding