A genome-wide association scan identifies several maternal susceptbility loci for embryo aneuploidy

Abstract

OBJECTIVE: To locate genetic variation which may be significantly associated with the proportion of embryo aneuploidy in a cohort of female IVF patients. DESIGN: Prospective observational. Caucasian female IVF patients were genotyped by microarray. Genome-wide association analysis was performed for genotypes against the proportion of aneuploid embryos obtained during a single cycle. MATERIALS AND METHODS: Female Caucasian IVF patients (n1⁄458) were selected for age ( 2, mean1⁄410). The proportion of aneuploid embryos in a single cycle was used as the dependent variable (mean1⁄438.5%). All subjects were genotyped using Affymetrix 250K Nsp arrays. SNPs were filtered using standard QC criteria (HWE p>0.001, MAF>0.03, CR>0.85). Stratification was corrected by principal component analysis. Genomewide regression models of genotypic association were calculated (additive, recessive, and dominant). Resulting regression p-values were adjusted for multiple testing (Bonferroni). RESULTS: After regression analysis and MT correction, 13 SNPs remained significantly associated (p<0.05) with the proportion of aneuploidy in female IVF patient embryos: 5 in additive, 2 in recessive and 6 in dominant models. Of the 13, 2 SNPs (rs1535208, chr20q12, and rs2506350, chr9q31.1) had corrected p<0.01, and nearby genes included some known as important to mitotic function such as topoisomerase 1 (TOP1) and structural maintenance of chromosomes 2 (SMC2). Genes near the other SNPs (<5MB) include SMC5, CENPN, BMI1, POT1, PTTG1, DBF4, and MAP1B, all which may have roles in maintaining chromosomal integrity, sister chromatid separation, and overall mitotic function. CONCLUSION: This is the first study to show a genetic predisposition to the maternal contribution to embryonic aneuploidy. Genes near associated SNPs may add biological context and provide avenues for future study. Ongoing accrual of data will increase power and provide an opportunity to replicate and refine these statistical associations.