Abstract
Infertility is one of the important problems in the modern world. Male infertility is characterized by several clinical manifestations, including low sperm production (oligozoospermia), reduced sperm motility (asthenozoospermia), and abnormal sperm morphology (teratozoospermia). WDR4, known as Wuho, controls fertility in Drosophila. However, it is unclear whether WDR4 is associated with clinical manifestations of male fertility in human. Here, we attempted to determine the physiological functions of WDR4 gene. Two cohorts were applied to address this question. The first cohort was the general population from Taiwan Biobank. Genomic profiles from 68,948 individuals and 87 common physiological traits were applied for phenome-wide association studies (PheWAS). The second cohort comprised patients with male infertility from Wan Fang Hospital, Taipei Medical University. In total, 81 male participants were recruited for the genetic association study. Clinical records including gender, age, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total sperm number, sperm motility, and sperm morphology were collected. In the first cohort, results from PheWAS exhibited no associations between WDR4 genetic variants and 87 common physiological traits. In the second cohort, a total of four tagging single-nucleotide polymorphisms (tSNPs) from WDR4 gene (rs2298666, rs465663, rs2248490, and rs3746939) were selected for genotyping. We found that SNP rs465663 solely associated with asthenozoospermia. Functional annotations through the GTEx portal revealed the correlation between TT or TC genotype and low expression of WDR4. Furthermore, we used mouse embryonic fibroblasts cells from mwdr4 heterozygous (+/‒) mice for functional validation by western blotting. Indeed, low expression of WDR4 contributed to ROS-induced DNA fragmentation. In conclusion, our results suggest a critical role of WDR4 gene variant as well as protein expression in asthenozoospermia.
Highlights
Infertility is defined as a disease characterized by the inability of couples to conceive a pregnancy after 12 months of regular unprotected intercourse [1]
The associations between 105 variants of WDR4 gene and 87 phenotypes were tested through the phenome-wide association studies (PheWAS)
A variety of associations between the WDR4 genetic variants and the common phenotypes were identified at the significance level of p < 0.05
Summary
Infertility is defined as a disease characterized by the inability of couples to conceive a pregnancy after 12 months of regular unprotected intercourse [1]. Infertility is a global health issue affecting 8~12% of couples worldwide, and male infertility factors are responsible for about 20~30% of infertility cases. 7% of the male population is affected by infertility [2]. Evaluating male infertility is mainly based on semen analyses. The most significant abnormalities of semen quality include a low sperm number (oligozoospermia), poor sperm motility (asthenozoospermia), and abnormal sperm morphology (teratozoospermia) [3,4]. Oxidative stress has been considered as a critical factor to infertility that possibly associated with the DNA fragmentation [5]. The DNA fragmentation levels were reported to correlate with sperm motility [6]
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