全基因组分析揭示25个不孕不育相关基因位点及其与等位基因频率谱中生殖性状的关联，这一成果由英国牛津大学Cecilia M. Lindgren研究小组经过不懈努力而取得。相关论文于2025年4月14日发表在《自然—遗传学》杂志上。

该研究组对多达42629例病例和740619例对照的7个队列进行了GWAS荟萃分析，确定了25个男性和女性不育的遗传风险位点。此外，通过性别特异性GWAS荟萃分析（n = 6095-246862），该研究团队发现了多达269个与卵泡刺激素、黄体生成素、雌二醇和睾酮相关的基因位点。外显子组测序分析显示，在某些基因中携带睾酮降低罕见变异的女性有不孕的风险。

然而，该课题组没有发现女性不育与生殖激素之间的局部或全基因组遗传相关性。虽然不孕症与子宫内膜异位症和多囊卵巢综合征在遗传上相关，但该研究团队发现不孕症和肥胖之间的遗传重叠有限。最后，课题组证明了不育风险等位基因的进化持久性可以用定向选择来解释。综上所述，小组提供了不孕不育的多种诊断标准的遗传决定因素的综合观点。

据介绍，全基因组关联研究（GWASs）可能有助于了解不孕症的病因。

附：英文原文

Title: Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum

Author: Venkatesh, Samvida S., Wittemans, Laura B. L., Palmer, Duncan S., Baya, Nikolas A., Ferreira, Teresa, Hill, Barney, Lassen, Frederik Heymann, Parker, Melody J., Reibe, Saskia, Elhakeem, Ahmed, Banasik, Karina, Bruun, Mie T., Erikstrup, Christian, Aagard Jensen, Bitten, Juul, Anders, Mikkelsen, Christina, Nielsen, Henriette S., Ostrowski, Sisse R., Pedersen, Ole B., Rohde, Palle Duun, Srensen, Erik, Ullum, Henrik, Westergaard, David, Haraldsson, Asgeir, Holm, Hilma, Jonsdottir, Ingileif, Olafsson, Isleifur, Steingrimsdottir, Thora, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Figueredo, Jessica, Karjalainen, Minna K., Pasanen, Anu, Jacobs, Benjamin M., Kalantzis, Georgios, Hubers, Nikki, Lippincott, Margaret, Fraser, Abigail, Lawlor, Deborah A., Timpson, Nicholas J., Nyegaard, Mette, Stefansson, Kari, Magi, Reedik, Laivuori, Hannele, van Heel, David A., Boomsma, Dorret I., Balasubramanian, Ravikumar, Seminara, Stephanie B., Chan, Yee-Ming, Laisk, Triin, Lindgren, Cecilia M.

Issue&Volume: 2025-04-14

Abstract: Genome-wide association studies (GWASs) may help inform the etiology of infertility. Here, we perform GWAS meta-analyses across seven cohorts in up to 42,629 cases and 740,619 controls and identify 25 genetic risk loci for male and female infertility. We additionally identify up to 269 genetic loci associated with follicle-stimulating hormone, luteinizing hormone, estradiol and testosterone through sex-specific GWAS meta-analyses (n=6,095–246,862). Exome sequencing analyses reveal that women carrying testosterone-lowering rare variants in some genes are at risk of infertility. However, we find no local or genome-wide genetic correlation between female infertility and reproductive hormones. While infertility is genetically correlated with endometriosis and polycystic ovary syndrome, we find limited genetic overlap between infertility and obesity. Finally, we show that the evolutionary persistence of infertility-risk alleles may be explained by directional selection. Taken together, we provide a comprehensive view of the genetic determinants of infertility across multiple diagnostic criteria.

DOI: 10.1038/s41588-025-02156-8

Source: https://www.nature.com/articles/s41588-025-02156-8