Abstract：
Approximately 70% of infertile men are diagnosed with idiopathic (abnormal semen parameters) or unexplained (normozoospermia) infertility, with the common feature of lacking etiologic factors. Follicle-stimulating hormone (FSH) is essential for initiation and maintenance of spermatogenesis. Certain single-nucleotide variations (SNVs; formerly single-nucleotide polymorphisms [SNPs]) (ie, FSHB c.-211G > T, FSHR c.2039A > G) are associated with FSH, testicular volume, and spermatogenesis. It is unknown to what extent other variants are associated with FSH levels and therewith resemble causative factors for infertility.
We aimed to identify further genetic determinants modulating FSH levels in a cohort of men presenting with idiopathic or unexplained infertility.
We retrospectively (2010-2018) selected 1900 men with idiopathic/unexplained infertility. In the discovery study (n = 760), a genome-wide association study (GWAS) was performed (Infinium PsychArrays) in association with FSH values (Illumina GenomeStudio, v2.0). Minor allele frequencies (MAFs) were analyzed for the discovery and an independent normozoospermic cohort. In the validation study (n = 1140), TaqMan SNV polymerase chain reaction was conducted for rs11031005 and rs10835638 in association with andrological parameters.
Imputation revealed 9 SNVs in high linkage disequilibrium, with genome-wide significance (P < 4.28e-07) at the FSHB locus 11p.14.1 being associated with FSH. The 9 SNVs accounted for up to a 4.65% variance in FSH level. In the oligozoospermic subgroup, this was increased up to 6.95% and the MAF was enhanced compared to an independent cohort of normozoospermic men. By validation, a significant association for rs11031005/rs10835638 with FSH (P = 4.71e-06/5.55e-07) and FSH/luteinizing hormone ratio (P = 2.08e-12/6.4e-12) was evident.
This GWAS delineates the polymorphic FSHB genomic region as the main determinant of FSH levels in men with unexplained or idiopathic infertility. Given the essential role of FSH, molecular detection of one of the identified SNVs that causes lowered FSH and therewith decreases spermatogenesis could resolve the idiopathic/unexplained origin by this etiologic factor.
We aimed to identify further genetic determinants modulating FSH levels in a cohort of men presenting with idiopathic or unexplained infertility.
We retrospectively (2010-2018) selected 1900 men with idiopathic/unexplained infertility. In the discovery study (n = 760), a genome-wide association study (GWAS) was performed (Infinium PsychArrays) in association with FSH values (Illumina GenomeStudio, v2.0). Minor allele frequencies (MAFs) were analyzed for the discovery and an independent normozoospermic cohort. In the validation study (n = 1140), TaqMan SNV polymerase chain reaction was conducted for rs11031005 and rs10835638 in association with andrological parameters.
Imputation revealed 9 SNVs in high linkage disequilibrium, with genome-wide significance (P < 4.28e-07) at the FSHB locus 11p.14.1 being associated with FSH. The 9 SNVs accounted for up to a 4.65% variance in FSH level. In the oligozoospermic subgroup, this was increased up to 6.95% and the MAF was enhanced compared to an independent cohort of normozoospermic men. By validation, a significant association for rs11031005/rs10835638 with FSH (P = 4.71e-06/5.55e-07) and FSH/luteinizing hormone ratio (P = 2.08e-12/6.4e-12) was evident.
This GWAS delineates the polymorphic FSHB genomic region as the main determinant of FSH levels in men with unexplained or idiopathic infertility. Given the essential role of FSH, molecular detection of one of the identified SNVs that causes lowered FSH and therewith decreases spermatogenesis could resolve the idiopathic/unexplained origin by this etiologic factor.
摘要：
大约70％的不育男性被诊断为特发性（精液参数异常）或无法解释的（正常精子症）不育，具有缺乏病因的共同特征。卵泡刺激素(FSH)对于启动和维持精子发生至关重要。某些单核苷酸变异（SNV；以前的单核苷酸多态性[SNP]）（即，FSHBc.-211G>T，FSHRc.2039A>G)与FSH相关，睾丸体积,和精子发生。尚不清楚其他变体与FSH水平相关的程度，因此与不孕症的致病因素相似。
我们的目的是在一组患有特发性或无法解释的不孕症的男性中进一步确定调节FSH水平的遗传决定因素。
我们回顾性地（2010-2018年）选择了1900名特发性/无法解释的不孕症男性。在发现研究中（n=760），与FSH值(IlluminaGenomeStudio，v2.0)。分析了次要等位基因频率（MAF）的发现和独立的正常精子症队列。在验证研究中（n=1140），对rs11031005和rs10835638进行TaqManSNV聚合酶链反应，并结合男性参数。
归因显示9个SNV处于高连锁不平衡状态，在FSHB基因座11p.14.1处具有全基因组意义（P<4.28e-07），与FSH相关。9个SNV占FSH水平的4.65%差异。在少精子症亚组中，与一个独立的正常精子症男性队列相比,这一比例增加了6.95%,MAF增强.通过验证，rs11031005/rs10835638与FSH(P=4.71e-06/5.55e-07)和FSH/黄体生成素比值(P=2.08e-12/6.4e-12)存在显著相关性.
这个GWAS描述了多态性FSHB基因组区域是不明原因或特发性不育症男性FSH水平的主要决定因素。鉴于FSH的重要作用，对已鉴定的SNV之一进行分子检测，该SNV导致FSH降低并由此减少精子发生，可以解决该病因的特发性/无法解释的起源。
我们的目的是在一组患有特发性或无法解释的不孕症的男性中进一步确定调节FSH水平的遗传决定因素。
我们回顾性地（2010-2018年）选择了1900名特发性/无法解释的不孕症男性。
归因显示9个SNV处于高连锁不平衡状态，
这个GWAS描述了多态性FSHB基因组区域是不明原因或特发性不育症男性FSH水平的主要决定因素。
