Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (P≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility (rg=0.585, P=8.98E-14), and between polycystic ovary syndrome and anovulatory infertility (rg=0.403, P=2.16E-03). The evolutionary persistence of female infertility-risk alleles in EBAG9 may be explained by recent directional selection. We additionally identified up to 269 genetic loci associated with follicle-stimulating hormone (FSH), luteinising hormone, oestradiol, and testosterone through sex-specific GWAS meta-analyses (N=6,095-246,862). While hormone-associated variants near FSHB and ARL14EP colocalised with signals for anovulatory infertility, we found no genetic correlation between female infertility and reproductive hormones (P>0.05). Exome sequencing analyses in the UK Biobank (N=197,340) revealed that women carrying testosterone-lowering rare variants in GPC2 were at higher risk of infertility (OR=2.63, P=1.25E-03). Taken together, our results suggest that while individual genes associated with hormone regulation may be relevant for fertility, there is limited genetic evidence for correlation between reproductive hormones and infertility at the population level. We provide the first comprehensive view of the genetic architecture of infertility across multiple diagnostic criteria in men and women, and characterise its relationship to other health conditions.

中文翻译：

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全基因组分析确定了等位基因频谱中的 21 个不育基因座和 400 多个生殖激素基因座

全基因组关联研究（GWAS）可能有助于为不孕症的治疗提供信息，在许多情况下，不孕症的原因仍不清楚。在这里，我们展示了六个队列的 GWAS 荟萃分析，涉及多达 41,200 例男性和女性不孕症病例和 687,005 名对照者。我们确定了 21 个不育遗传风险位点 (P≤5E-08)，其中 12 个尚未报告任何生殖状况。我们发现子宫内膜异位症与全因女性不孕症之间存在正向遗传相关性（rg=0.585，P=8.98E-14），多囊卵巢综合征与无排卵性不孕症之间存在正向遗传相关性（rg=0.403，P=2.16E-03）。 EBAG9 中女性不孕风险等位基因的进化持续性可以通过最近的定向选择来解释。我们还通过性别特异性 GWAS 荟萃分析确定了多达 269 个与卵泡刺激素 (FSH)、黄体生成素、雌二醇和睾酮相关的基因位点 (N=6,095-246,862)。虽然 FSHB 和 ARL14EP 附近的激素相关变异与无排卵不孕症信号共存，但我们发现女性不孕症与生殖激素之间没有遗传相关性（P>0.05）。英国生物银行的外显子组测序分析 (N=197,340) 显示，携带 GPC2 中睾酮降低的罕见变异的女性不孕风险较高 (OR=2.63，P=1.25E-03)。综上所述，我们的结果表明，虽然与激素调节相关的个体基因可能与生育力相关，但在人群水平上生殖激素与不孕症之间相关性的遗传证据有限。我们首次全面了解男性和女性多种诊断标准的不孕症遗传结构，并描述了其与其他健康状况的关系。