# Common variation in meiosis genes shapes human recombination and aneuploidy

## TL;DR

This study identifies genetic variants linked to meiotic errors that cause aneuploidy, a major cause of pregnancy loss.

## Contribution

The study reveals a common haplotype in SMC1B and other genes that influence both recombination and aneuploidy risk.

## Key findings

- A common haplotype in SMC1B is associated with crossover count and maternal meiotic aneuploidy.
- Variants in C14orf39, CCNB1IP1, and RNF212 are linked to meiotic aneuploidy risk.
- Aneuploidy-associated variants also show connections to recombination and reproductive aging traits.

## Abstract

The leading cause of human pregnancy loss is aneuploidy, often tracing to errors in chromosome segregation during female meiosis1,2. Although abnormal crossover recombination is known to confer risk for aneuploidy3,4, 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 pre-implantation genetic testing data from 139,416 in vitro fertilized embryos from 22,850 sets of biological parents. By tracing transmission of haplotypes, we identified 3,809,412 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 associated significantly 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, variants associated with aneuploidy often showed secondary associations with recombination, and several also exhibited associations with reproductive ageing traits. Our findings highlight the dual role of recombination in generating genetic diversity, while ensuring meiotic fidelity.

Analysis of data from pre-implantation genetic testing sheds light on the genetic basis of meiotic-origin aneuploidy, the leading cause of human pregnancy loss, identifying common genetic variants associated with maternal meiotic errors.