• PMID: 26199320
• Gene Name: FKBPL
• Condition: Non-obstructive azoospermia
• Association: Associated
• Mutation: rs200847762 (p.Pro137Leu)
• Population size: 9726
• Population details: 9726 (3130 cases, 6596 controls)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Low-frequency germline variants across 6p22.2-6p21.33 are associated with non-obstructive azoospermia in Han Chinese men

Ni B, Lin Y, Sun L, Zhu M, Li Z, Wang H, Yu J, Guo X, Zuo X, Dong J, Xia Y, Wen Y, Wu H, Li H, Zhu Y, Ping P, Chen X, Dai J, Jiang Y, Xu P, Du Q, Yao B, Weng N, Lu H, Wang Z, Zhu X, Yang X, Xiong C, Ma H, Jin G, Xu J, Wang X, Zhou Z, Liu J, Zhang X, Conrad DF, Hu Z, Sha J.

Genome-wide association studies (GWAS) have identified several common loci contributing to non-obstructive azoospermia (NOA). However, a substantial fraction of NOA heritability remains undefined, especially those low-frequency [defined here as having a minor allele frequency (MAF) between 0.5 and 5%] and rare (MAF below 0.5%) variants. Here, we performed a 3-stage exome-wide association study in Han Chinese men to evaluate the role of low-frequency or rare germline variants in NOA development. The discovery stage included 962 NOA cases and 1348 healthy male controls genotyped by exome chips and was followed by a 2-stage replication with an additional 2168 cases and 5248 controls. We identified three low-frequency variants located at 6p22.2 (rs2298090 in HIST1H1E encoding p.Lys152Arg: OR = 0.30, P = 2.40 × 10(-16)) and 6p21.33 (rs200847762 in FKBPL encoding p.Pro137Leu: OR = 0.11, P = 3.77 × 10(-16); rs11754464 in MSH5: OR = 1.78, P = 3.71 × 10(-7)) associated with NOA risk after Bonferroni correction. In summary, we report an instance of newly identified signals for NOA risk in genes previously undetected through GWAS on 6p22.2-6p21.33 in a Chinese population and highlight the role of low-frequency variants with a large effect in the process of spermatogenesis. CI - © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Ni, Bixian AU - Ni B AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Lin, Yuan AU - Lin Y AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Sun, Liangdan AU - Sun L AD - Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230022, China, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui 230022, China. FAU - Zhu, Meng AU - Zhu M AD - Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Li, Zheng AU - Li Z AD - Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. FAU - Wang, Hui AU - Wang H AD - Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Yu, Jun AU - Yu J AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China. FAU - Guo, Xuejiang AU - Guo X AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China. FAU - Zuo, Xianbo AU - Zuo X AD - Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230022, China, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui 230022, China. FAU - Dong, Jing AU - Dong J AD - Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Xia, Yankai AU - Xia Y AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Toxicology and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China. FAU - Wen, Yang AU - Wen Y AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Wu, Hao AU - Wu H AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China. FAU - Li, Honggang AU - Li H AD - Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China. FAU - Zhu, Yong AU - Zhu Y AD - Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. FAU - Ping, Ping AU - Ping P AD - Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. FAU - Chen, Xiangfeng AU - Chen X AD - Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. FAU - Dai, Juncheng AU - Dai J AD - Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Jiang, Yue AU - Jiang Y AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Xu, Peng AU - Xu P AD - Jinghua Hospital, Shenyang Dongfang Medical Group, Shenyang 110004, China. FAU - Du, Qiang AU - Du Q AD - Department of Reproduction, Shengjing Hospital, China Medical University, Shenyang 110004, China. FAU - Yao, Bing AU - Yao B AD - Department of Andrology, Nanjing Jinling Hospital, Nanjing 210029, China. FAU - Weng, Ning AU - Weng N AD - Jinghua Hospital, Shenyang Dongfang Medical Group, Shenyang 110004, China. FAU - Lu, Hui AU - Lu H AD - Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. FAU - Wang, Zhuqing AU - Wang Z AD - Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. FAU - Zhu, Xiaobin AU - Zhu X AD - Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. FAU - Yang, Xiaoyu AU - Yang X AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China. FAU - Xiong, Chenliang AU - Xiong C AD - Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China. FAU - Ma, Hongxia AU - Ma H AD - Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Jin, Guangfu AU - Jin G AD - Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and. FAU - Xu, Jianfeng AU - Xu J AD - Department of Urology, Huashan Hospital, Shanghai 200052, China. FAU - Wang, Xinru AU - Wang X AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Toxicology and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China. FAU - Zhou, Zuomin AU - Zhou Z AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China. FAU - Liu, Jiayin AU - Liu J AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Center of Clinical Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China. FAU - Zhang, Xuejun AU - Zhang X AD - Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui 230022, China, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, China, Hefei, Anhui 230022, China. FAU - Conrad, Donald F AU - Conrad DF AD - Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, USA, Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO 63110, USA. FAU - Hu, Zhibin AU - Hu Z AD - State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health and State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200052, China, zhibin_hu@njmu.edu.cn shajh@njmu.edu.cn.