Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men.
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.
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].
Zhibin
Z
Hu
1] Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China [2].
Zheng
Z
Li
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].
Jun
J
Yu
1] Institute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang University, Hangzhou 310058, China [2].
Chao
C
Tong
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].
Yuan
Y
Lin
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].
Xuejiang
X
Guo
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.
Feng
F
Lu
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.
Jing
J
Dong
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.
Yankai
Y
Xia
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.
Yang
Y
Wen
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.
Hao
H
Wu
Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
Honggang
H
Li
Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Yong
Y
Zhu
Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Ping
P
Ping
Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Xiangfeng
X
Chen
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.
Juncheng
J
Dai
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.
Yue
Y
Jiang
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.
Shandong
S
Pan
Jinghua Hospital, Shenyang Dongfang Medical Group, Shenyang 110004, China.
Peng
P
Xu
Reproductive Medical Center, The Second Hospital of Nanning, Nanning 530022, China.
Kailing
K
Luo
Department of Reproduction, Shengjing Hospital, China Medical University, Shenyang 110004, China.
Qiang
Q
Du
Department of Andrology, Nanjing Jinling Hospital, Nanjing 210029, China.
Bing
B
Yao
The Second Affiliated Hospital, Shandong University of Traditional Chinese Medicine, Shandong 250033, China.
Ming
M
Liang
Guangdong Key Laboratory of Male Reproductive Medicine and Genetics, Peking University Shenzhen Hospital, FuTian District, Shenzhen 518035, China.
Yaoting
Y
Gui
Jinghua Hospital, Shenyang Dongfang Medical Group, Shenyang 110004, China.
Ning
N
Weng
Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Hui
H
Lu
Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Zhuqing
Z
Wang
The Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
Fengbin
F
Zhang
Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Xiaobin
X
Zhu
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.
Xiaoyu
X
Yang
Maternal and Child Health Hospital of Shanxi Province, Xian 300013, China.
Zhou
Z
Zhang
Center for Reproductive Medicine, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
Han
H
Zhao
Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
Chenliang
C
Xiong
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.
Hongxia
H
Ma
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.
Guangfu
G
Jin
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.
Feng
F
Chen
Department of Urology, Huashan Hospital, Fudan University, Shanghai 200052, China.
Jianfeng
J
Xu
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.
Xinru
X
Wang
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.
Zuomin
Z
Zhou
Center for Reproductive Medicine, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
Zi-Jiang
ZJ
Chen
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.
Jiayin
J
Liu
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.
Hongbing
H
Shen
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.
Jiahao
J
Sha
D000818:Animals; D053713:Azoospermia / Q000235:genetics*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015203:Reproducibility of Results; D012307:Risk Factors
D029721:Drosophila Proteins; C109463:Gek protein, Drosophila; D017346:Protein Serine-Threonine Kinases