{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T14:24:26Z","timestamp":1776522266103,"version":"3.51.2"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Health and welfare surcharge of tobacco products","award":["MOHW110-TDU-B-212-144014; MOHW110-TDU-B-212-144020"],"award-info":[{"award-number":["MOHW110-TDU-B-212-144014; MOHW110-TDU-B-212-144020"]}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST109-2314-B-038-131 and MOST109-2628-B-038-012"],"award-info":[{"award-number":["MOST109-2314-B-038-131 and MOST109-2628-B-038-012"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taipei Medical University, Taiwan","award":["12310-106079; Yusuke Nakamura Chair Professorship"],"award-info":[{"award-number":["12310-106079; Yusuke Nakamura Chair Professorship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>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 (+\/\u2012) 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.<\/jats:p>","DOI":"10.3390\/jpm11080760","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T12:59:24Z","timestamp":1627649964000},"page":"760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genetic Association of the Functional WDR4 Gene in Male Fertility"],"prefix":"10.3390","volume":"11","author":[{"given":"Yu-Jia","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eko","family":"Mugiyanto","sequence":"additional","affiliation":[{"name":"PhD Program in Clinical Drug Development of Chinese Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Ting","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan-Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7693-5959","authenticated-orcid":false,"given":"Wan-Hsuan","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Chiu","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Shiuan","family":"Wang","sequence":"additional","affiliation":[{"name":"PhD Program in Clinical Drug Development of Chinese Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lalu Muhammad","family":"Irham","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Faculty of Pharmacy, University of Ahmad Dahlan, Yogyakarta 55164, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dyah Aryani","family":"Perwitasari","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Ahmad Dahlan, Yogyakarta 55164, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-I","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Chiao","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"},{"name":"Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1016\/j.fertnstert.2009.09.009","article-title":"International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009","volume":"92","author":"Adamson","year":"2009","journal-title":"Fertil. 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