Ruotsalainen Sanni, Karjalainen Juha, Kurki Mitja, Lahtela Elisa, Pirinen Matti, Riikonen Juha, Ritari Jarmo, Tammi Silja, Partanen Jukka, Laivuori Hannele, Palotie Aarno, Heyne Henrike, Daly Mark, Widen Elisabeth
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Program for Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Am J Hum Genet. 2024 Dec 5;111(12):2789-2798. doi: 10.1016/j.ajhg.2024.10.018. Epub 2024 Nov 19.
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). 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). 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.
女性不孕症是一个常见且复杂的健康问题，影响着全球数百万女性。虽然多种因素可导致这种情况，但在多达15%-30%的受影响个体中，潜在原因仍不明确。在我们对芬兰人群队列FinnGen中22849名不孕女性和198989名对照个体进行的大规模全基因组关联研究（GWAS）中，我们揭示了与该疾病相关的遗传因素情况。我们的隐性分析在类TATA盒结合蛋白2（TBPL2；c.895A>T [p.Arg299Ter]；次要等位基因频率[MAF]=1.2%）中发现了一个低频的获得性终止突变，其影响与高 penetrance 的单基因突变异（比值比[OR]=650，p=4.1×10）相当。虽然先前的研究已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，但携带该变体两个拷贝的个体与其他基因型组的女性相比，后代明显更少（平均0.16个），这证明了p.Arg299Ter变体的严重后果（其他基因型组女性平均有1.75个后代，p=1.4×10）。值得注意的是，所有已生育的纯合女性都接受了不孕症治疗。此外，我们按年龄分层的分析还确定了另外三个全基因组显著位点。两个位点与早发性不孕症（30岁之前诊断）相关，分别位于CHEK2附近和主要组织相容性复合体（MHC）区域内。第三个位点与晚发性不孕症相关，其领先单核苷酸多态性（SNP）位于一个长链非编码RNA（lncRNA）基因的内含子中。综上所述，我们的数据突出了罕见隐性等位基因在塑造女性不孕风险方面的重要性。这些结果进一步提供了证据，支持了这种复杂疾病背后特定的年龄依赖性机制。
