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

Bixian Ni, Yuan Lin, Liangdan Sun, Meng Zhu, Zheng Li, Hui Wang, Jun Yu, Xuejiang Guo, Xianbo Zuo, Jing Dong, Yankai Xia, Yang Wen, Hao Wu, Honggang Li, Yong Zhu, Ping Ping, Xiangfeng Chen, Juncheng Dai, Yue Jiang, Peng XuQiang Du, Bing Yao, Ning Weng, Hui Lu, Zhuqing Wang, Xiaobin Zhu, Xiaoyu Yang, Chenliang Xiong, Hongxia Ma, Guangfu Jin, Jianfeng Xu, Xinru Wang, Zuomin Zhou, Jiayin Liu, Xuejun Zhang, Donald F. Conrad, Zhibin Hu, Jiahao Sha

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5628-5636
Number of pages9
JournalHuman molecular genetics
Issue number19
StatePublished - Oct 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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