deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
School of Technology, Reykjavik University, Reykjavik, Iceland.
Nat Struct Mol Biol. 2024 Apr;31(4):710-716. doi: 10.1038/s41594-023-01209-y. Epub 2024 Jan 29.
Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 (SYCE2), in a key residue for the assembly of the synaptonemal complex backbone, associates with recombination traits. Here we show that it also increases risk of pregnancy loss in a genome-wide association analysis on 114,761 women with reported pregnancy loss. We further show that the variant associates with more random placement of crossovers and lower recombination rate in longer chromosomes but higher in the shorter ones. These results support the hypothesis that some pregnancy losses are due to failures in recombination. They further demonstrate that variants with a substantial effect on the quality of recombination can be maintained in the population.
三分之二的人类妊娠会发生丢失,在大多数情况下,这种丢失发生在临床检测之前。由于缺乏对妊娠丢失原因的详细了解,限制了针对未来妊娠的有针对性的咨询。我们之前已经表明,在一个关键残基上组装联会复合体骨架的联会复合体中心蛋白 2(SYCE2)中的错义变体与重组特征相关。在这里,我们在 114761 名报告有妊娠丢失的女性中进行全基因组关联分析,结果显示该变体也会增加妊娠丢失的风险。我们进一步表明,该变体与更多随机放置的交叉点和更长染色体上的较低重组率相关,但在较短染色体上的重组率较高。这些结果支持这样一种假说,即一些妊娠丢失是由于重组失败所致。它们进一步表明,对重组质量有重大影响的变体可以在人群中得以维持。