Common variation in meiosis genes shapes human recombination phenotypes and aneuploidy risk

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Abstract
The leading cause of human pregnancy loss is aneuploidy, often tracing to errors in chromosome segregation during female meiosis. While abnormal crossover recombination is known to confer risk for aneuploidy, limited data have hindered understanding of the potential shared genetic basis of these key molecular phenotypes. To address this gap, we performed retrospective analysis of preimplantation genetic testing data from 139,416 in vitro fertilized embryos from 22,850 sets of biological parents. By tracing transmission of haplotypes, we identified 3,656,198 crossovers, as well as 92,485 aneuploid chromosomes. Counts of crossovers were lower in aneuploid versus euploid embryos, consistent with their role in chromosome pairing and segregation. Our analyses further revealed that a common haplotype spanning the meiotic cohesin SMC1B is significantly associated with both crossover count and maternal meiotic aneuploidy, with evidence supporting a non-coding cis -regulatory mechanism. Transcriptome- and phenome-wide association tests also implicated variation in the synaptonemal complex component C14orf39 and crossover-regulating ubiquitin ligases CCNB1IP1 and RNF212 in meiotic aneuploidy risk. More broadly, recombination and aneuploidy possess a partially shared genetic basis that also overlaps with reproductive aging traits. Our findings highlight the dual role of recombination in generating genetic diversity, while ensuring meiotic fidelity.

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