Identification of candidate genes associated with mitotic-origin aneuploidy: a genome-wide association study

Aneuploidy is the most common genetic abnormality in human embryos and is one of the leading causes of embryo transfer failure. We aimed to identify candidate genes linked to mitotic-origin aneuploidy.

A control group of 588 euploid embryos and a case group of 236 mosaic embryos were utilized. Sequence alignment was first conducted to identify single nucleotide polymorphism (SNP) loci. Quality control (QC) and principal component analysis (PCA) were then performed to filter the SNPs and samples. The association test was carried out to identify significant variants. Fine mapping and gene sorting were used to screen and sort the candidate genes.

Following variant identification, 10,650,011 SNPs were detected in 824 enrolled embryos. After quality control (QC), principal component analysis (PCA), and imputation, 496,728 SNPs across 762 embryos (226 cases and 536 controls) were retained. Association analysis identified 70 SNPs reaching genome-wide significance (p < 5e^-8). Following annotation, 37 variants within 27 genes were considered functional. Gene Ontology (GO) analysis revealed enrichment in innate immune and protein homeostasis pathways. Fine mapping and gene prioritization highlighted EMP2 as a candidate gene of mitotic error. We found that EMP2 may play a critical role in cell-cycle control and endometrial receptivity.

In this study, we performed genome-wide association analysis on embryonic sequencing data and identified EMP2 on chromosome 16 as a potential gene implicated in mitotic-origin aneuploidy. Further verification experiments are required to confirm the functions of candidate genes during embryogenesis.