全基因组分析确定了25个不育基因座以及等位基因频率谱上与生殖性状的关系。
Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum.
作者信息
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, Sørensen 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
机构信息
Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
出版信息
Nat Genet. 2025 May;57(5):1107-1118. doi: 10.1038/s41588-025-02156-8. Epub 2025 Apr 14.
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.
全基因组关联研究（GWAS）可能有助于揭示不孕症的病因。在此，我们对多达7个队列中的42629例病例和740619例对照进行了GWAS荟萃分析，并确定了25个男性和女性不孕症的遗传风险位点。我们还通过性别特异性GWAS荟萃分析（n = 6095 - 246862）确定了多达269个与促卵泡激素、促黄体生成素、雌二醇和睾酮相关的遗传位点。外显子组测序分析表明，携带某些基因中降低睾酮的罕见变异的女性存在不孕风险。然而，我们发现女性不孕症与生殖激素之间不存在局部或全基因组的遗传相关性。虽然不孕症与子宫内膜异位症和多囊卵巢综合征存在遗传相关性，但我们发现不孕症与肥胖之间的遗传重叠有限。最后，我们表明不孕症风险等位基因的进化持续性可能由定向选择来解释。综上所述，我们提供了一个跨越多种诊断标准的不孕症遗传决定因素的全面视图。
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