Identification of genetic loci associated with the risk of aneuploidy with maternal origin using PGT

Siqi Sun1 , Aishee Bag1 , Daniel Ariad2 , Mary Haywood3 , Mandy Katz-Jaffe3 , Rajiv McCoy2 , Karen Schindler1, 4, Jinchuan Xing1, 4 1Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. 2Department of Biology, Johns Hopkins University, Baltimore, MD, USA. 3CCRM Genetics, Lone Tree, CO, USA. 4Human Genetic Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.

Aneuploidy, the inheritance of extra or missing chromosomes, frequently arises during human meiosis and is the primary cause of early miscarriage and maternally age-related in vitro fertilization (IVF) failure. The exact genetic causes of variability in aneuploid egg production remain unclear despite the discovery of several genetic variants that predispose women to a higher incidence of meiotic aneuploidy. Preimplantation genetic testing for aneuploidy (PGT-A) with low-coverage whole-genome sequencing (lc-WGS) is a standard test for selecting IVF embryos with a normal chromosome complement. The wealth of embryo aneuploidy rate data and lc-WGS data from PGT-A can potentially be used to identify novel loci associated with aneuploidy. By combining lc-WGS data from full-sibling embryos, we imputed genotype likelihoods of genetic variants in parental genomes. We then used these imputed data, as well as aneuploidy calls from the embryos to perform a genome-wide association study of aneuploidy rates. We identified one locus on chromosome 3 that is associated with maternal meiotic aneuploidy risk. Several candidate genes (e.g., ERC2 and CCDC66) encompassed by this locus are known to be involved in chromosome segregation during meiosis. Together, our work improves the understanding of the genetic basis of maternal meiotic aneuploidy risk, while introducing a generalizable method that can be leveraged for similar association studies of lc-WGS data.