Female infertility is a common and complex health problem affecting millions of women worldwide. While multiple factors can contribute to this condition, the underlying cause remains elusive in up to 15%–30% of affected individuals. In our large genome-wide association study (GWAS) of 22,849 women with infertility and 198,989 control individuals from the Finnish population cohort FinnGen, we unveil a landscape of genetic factors associated with the disorder. Our recessive analysis identified a low-frequency stop-gained mutation in TATA-box binding protein-like 2 (TBPL2; c.895A>T [p.Arg299Ter]; minor-allele frequency [MAF] = 1.2%) with an impact comparable to highly penetrant monogenic mutations (odds ratio [OR] = 650, p = 4.1 × 10−25). While previous studies have linked the orthologous gene to anovulation and sterility in knockout mice, the severe consequence of the p.Arg299Ter variant was evidenced by individuals carrying two copies of that variant having significantly fewer offspring (average of 0.16) compared to women belonging to the other genotype groups (average of 1.75 offspring, p = 1.4 × 10−15). Notably, all homozygous women who had given birth had received infertility therapy. Moreover, our age-stratified analyses identified three additional genome-wide significant loci. Two loci were associated with early-onset infertility (diagnosed before age 30), located near CHEK2 and within the major histocompatibility complex (MHC) region. The third locus, associated with late-onset infertility, had its lead SNP located in an intron of a long non-coding RNA (lncRNA) gene. Taken together, our data highlight the significance of rare recessive alleles in shaping female infertility risk. The results further provide evidence supporting specific age-dependent mechanisms underlying this complex disorder.

中文翻译：

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遗传性不孕症：绘制与女性生殖受损相关的位点


女性不孕症是一个常见而复杂的健康问题，影响着全世界数百万女性。虽然多种因素可能导致这种情况，但在多达 15%-30% 的受影响个体中，根本原因仍然难以捉摸。在我们针对 22,849 名不孕症女性和来自芬兰人群队列 FinnGen 的 198,989 名对照个体的大型全基因组关联研究 （GWAS） 中，我们揭示了与该疾病相关的遗传因素的景观。我们的隐性分析确定了 TATA 盒结合蛋白样蛋白 2 （TBPL2;c.895A>T [p.Arg299Ter];次要等位基因频率 [MAF] = 1.2%）中的低频停止获得突变，其影响与高渗透性单基因突变相当 （比值比 [OR] = 650，p = 4.1 × 10-25）。虽然以前的研究将直系同源基因与基因敲除小鼠的无排卵和不育联系起来，但 p.Arg299Ter 变体的严重后果是通过携带该变体的两个拷贝的个体与属于其他基因型组的女性相比（平均 1.75 个后代，p = 1.4 × 10-15）的后代明显较少（平均 0.16）。值得注意的是，所有分娩的纯合子妇女都接受了不孕症治疗。此外，我们的年龄分层分析确定了另外三个全基因组的重要基因座。两个基因位点与早发性不孕症 （30 岁之前诊断） 相关，位于 CHEK2 附近和主要组织相容性复合体 （MHC） 区域内。第三个基因座与晚发性不孕症相关，其先导 SNP 位于长链非编码 RNA （lncRNA） 基因的内含子中。综上所述，我们的数据强调了稀有隐性等位基因在塑造女性不孕风险中的重要性。 结果进一步提供了支持这种复杂疾病背后的特定年龄依赖性机制的证据。