Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men

Zhibin Hu; Zheng Li; Jun Yu; Chao Tong; Yuan Lin; Xuejiang Guo; Feng Lu; Jing Dong; Yankai Xia; Yang Wen; Hao Wu; Honggang Li; Yong Zhu; Ping Ping; Xiangfeng Chen; Juncheng Dai; Yue Jiang; Shandong Pan; Peng Xu; Kailing Luo; Qiang Du; Bing Yao; Ming Liang; Yaoting Gui; Ning Weng; Hui Lu; Zhuqing Wang; Fengbin Zhang; Xiaobin Zhu; Xiaoyu Yang; Zhou Zhang; Han Zhao; Chenliang Xiong; Hongxia Ma; Guangfu Jin; Feng Chen; Jianfeng Xu; Xinru Wang; Zuomin Zhou; Zi-Jiang Chen; Jiayin Liu; Hongbing Shen; Jiahao Sha

doi:10.1038/ncomms4857

Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men

Nat Commun. 2014 May 23:5:3857. doi: 10.1038/ncomms4857.

Authors

Zhibin Hu¹, Zheng Li², Jun Yu³, Chao Tong⁴, Yuan Lin¹, Xuejiang Guo³, Feng Lu⁵, Jing Dong⁵, Yankai Xia⁶, Yang Wen⁷, Hao Wu⁸, Honggang Li⁹, Yong Zhu¹⁰, Ping Ping¹⁰, Xiangfeng Chen¹⁰, Juncheng Dai⁵, Yue Jiang⁷, Shandong Pan⁵, Peng Xu¹¹, Kailing Luo¹², Qiang Du¹³, Bing Yao¹⁴, Ming Liang¹⁵, Yaoting Gui¹⁶, Ning Weng¹¹, Hui Lu¹⁰, Zhuqing Wang¹⁰, Fengbin Zhang¹⁷, Xiaobin Zhu¹⁰, Xiaoyu Yang¹⁸, Zhou Zhang¹⁹, Han Zhao²⁰, Chenliang Xiong⁹, Hongxia Ma⁵, Guangfu Jin⁵, Feng Chen⁵, Jianfeng Xu²¹, Xinru Wang⁶, Zuomin Zhou⁸, Zi-Jiang Chen²⁰, Jiayin Liu¹⁸, Hongbing Shen⁷, Jiahao Sha⁸

Affiliations

¹ 1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China [2] Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China [3].
² 1] Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China [2].
³ 1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China [2] Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China [3].
⁴ 1] Institute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang University, Hangzhou 310058, China [2].
⁵ Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
⁶ 1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China [2] Department of Toxicology and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
⁷ 1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China [2] Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
⁸ 1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China [2] Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China.
⁹ Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
¹⁰ Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
¹¹ Jinghua Hospital, Shenyang Dongfang Medical Group, Shenyang 110004, China.
¹² Reproductive Medical Center, The Second Hospital of Nanning, Nanning 530022, China.
¹³ Department of Reproduction, Shengjing Hospital, China Medical University, Shenyang 110004, China.
¹⁴ Department of Andrology, Nanjing Jinling Hospital, Nanjing 210029, China.
¹⁵ The Second Affiliated Hospital, Shandong University of Traditional Chinese Medicine, Shandong 250033, China.
¹⁶ Guangdong Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, FuTian District, Shenzhen 518035, China.
¹⁷ The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
¹⁸ 1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China [2] Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
¹⁹ Maternal and Child Health Hospital of Shanxi Province, Xian 300013, China.
²⁰ Center for Reproductive Medicine, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
²¹ Department of Urology, Huashan Hospital, Fudan University, Shanghai 200052, China.

PMID: 24852083
DOI: 10.1038/ncomms4857

Abstract

Male factor infertility affects one-sixth of couples worldwide, and non-obstructive azoospermia (NOA) is one of the most severe forms. Our previous genome-wide association study (GWAS) identified three susceptibility loci for NOA in Han Chinese men. Here we test promising associations in an extended three-stage validation using 3,608 NOA cases and 5,909 controls to identify additional risk loci. We find strong evidence of three NOA susceptibility loci (P<5.0 × 10(-8)) at 6p21.32 (rs7194, P=3.76 × 10(-19)), 10q25.3 (rs7099208, P=6.41 × 10(-14)) and 6p12.2 (rs13206743, P=3.69 × 10(-8)), as well as one locus approaching genome-wide significance at 1q42.13 (rs3000811, P=7.26 × 10(-8)). In addition, we investigate the phenotypic effect of the related gene (gek, orthologous to CDC42BPA) at 1q42.13 on male fertility using a Drosophila model. These results advance our understanding of the genetic susceptibility to NOA and provide insights into its pathogenic mechanism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azoospermia / genetics*
Drosophila Proteins / metabolism
Drosophila melanogaster / genetics
Genetic Loci*
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Infertility, Male / genetics
Male
Polymorphism, Single Nucleotide / genetics
Protein Serine-Threonine Kinases / metabolism
Reproducibility of Results
Risk Factors

Substances

Drosophila Proteins
Gek protein, Drosophila
Protein Serine-Threonine Kinases

Supplementary concepts

Azoospermia, Nonobstructive