Abstract

Infertility is a growing concern in developed societies. Two extreme phenotypes of male infertility are non-obstructive azoospermia (NOA) and severe oligospermia (SO), which are characterized by severe spermatogenic failure (SpF). We designed a genetic association study comprising 725 Iberian infertile men as a consequence of SpF and 1058 unaffected controls to evaluate whether five single-nucleotide polymorphisms (SNPs), previously associated with reduced fertility in Hutterites, are also involved in the genetic susceptibility to idiopathic SpF and specific clinical entities. A significant difference in the allele frequencies of USP8-rs7174015 was observed under the recessive model between the NOA group and both the control group (p = 0.0226, OR = 1.33) and the SO group (p = 0.0048, OR = 1.78). Other genetic associations for EPSTI1-rs12870438 and PSAT1-rs7867029 with SO and between TUSC1-rs10966811 and testicular sperm extraction (TESE) success in the context of NOA were observed. In silico analysis of functional annotations demonstrated cis-eQTL effects of such SNPs likely due to the modification of binding motif sites for relevant transcription factors of the spermatogenic process. The findings reported here shed light on the molecular mechanisms leading to severe phenotypes of idiopathic male infertility, and may help to better understand the contribution of the common genetic variation to the development of these conditions.

Highlights

  • Male infertility is considered one of the major health concerns in developed societies, affecting 10–15% of couples of childbearing age worldwide

  • The genotyping success rate for every analyzed single-nucleotide polymorphisms (SNPs) was over 98%, and the minor allele frequencies (MAF) of the control groups were consistent with those of both the Iberian subpopulation (IBS) and the European super population (EUR) of the 1KGPh3 [18]

  • Our results suggest that both EPSTI1-rs12870438 and PSAT1-rs7867029 are involved in the pathological mechanisms underlying severe oligospermia (SO), whereas the intergenic SNP USP8-rs7174015 may contribute to the genetic susceptibility to non-obstructive azoospermia (NOA)

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Summary

Introduction

Male infertility is considered one of the major health concerns in developed societies, affecting 10–15% of couples of childbearing age worldwide. It has been reported that the two most extreme phenotypes of male infertility, i.e., severe oligospermia (SO, very low concentration of spermatozoa in semen) and non-obstructive azoospermia (NOA, complete lack of sperm in the ejaculate due to non-obstructive causes), have an important genetic component [2]. These two male infertility manifestations are characterized by severe spermatogenic impairment (SpF) and their known primary causes include different genetic alterations, such as point mutations on genes with key roles in the male gametogenesis process, Y-chromosome microdeletions, and karyotype abnormalities [3].

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