title: Low-frequency germline variants across 6p22.2-6p21.33 are associated with non-obstructive azoospermia in Han Chinese men.
abstract: 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.
authors.affiliation: 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.
authors.forename: Bixian
authors.initials: B
authors.lastname: Ni
authors.affiliation: 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.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Liangdan
authors.initials: L
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xuejiang
authors.initials: X
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Xianbo
authors.initials: X
authors.lastname: Zuo
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
authors.forename: Honggang
authors.initials: H
authors.lastname: Li
authors.affiliation: Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ping
authors.affiliation: Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Xiangfeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Dai
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Jinghua Hospital, Shenyang Dongfang Medical Group, Shenyang 110004, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Reproduction, Shengjing Hospital, China Medical University, Shenyang 110004, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Du
authors.affiliation: Department of Andrology, Nanjing Jinling Hospital, Nanjing 210029, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: Jinghua Hospital, Shenyang Dongfang Medical Group, Shenyang 110004, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Weng
authors.affiliation: Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
authors.affiliation: Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Shanghai Human Sperm Bank, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Family Planning Research Institute, Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, China.
authors.forename: Chenliang
authors.initials: C
authors.lastname: Xiong
authors.affiliation: 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.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Urology, Huashan Hospital, Shanghai 200052, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Zuomin
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.affiliation: 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.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China, Department of Histology and Embryology, Nanjing Medical University, Nanjing 210029, China, zhibin_hu@njmu.edu.cn shajh@njmu.edu.cn.
authors.forename: Jiahao
authors.initials: J
authors.lastname: Sha
mesh_terms: D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D053713:Azoospermia / Q000235:genetics*; D002681:China / Q000208:ethnology; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D059472:Exome; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide