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, Don Conrad, Zhibin Hu, Jiahao Sha

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberddv257
Pages (from-to)5628-5636
Number of pages9
JournalHuman molecular genetics
Volume24
Issue number19
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Azoospermia
Exome
Genome-Wide Association Study
Gene Frequency
Spermatogenesis
Population
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Low-frequency germline variants across 6p22.2-6p21.33 are associated with non-obstructive azoospermia in Han Chinese men. / Ni, Bixian; Lin, Yuan; Sun, Liangdan; Zhu, Meng; Li, Zheng; Wang, Hui; Yu, Jun; Guo, Xuejiang; Zuo, Xianbo; Dong, Jing; Xia, Yankai; Wen, Yang; Wu, Hao; Li, Honggang; Zhu, Yong; Ping, Ping; Chen, Xiangfeng; Dai, Juncheng; Jiang, Yue; Xu, Peng; Du, Qiang; Yao, Bing; Weng, Ning; Lu, Hui; Wang, Zhuqing; Zhu, Xiaobin; Yang, Xiaoyu; Xiong, Chenliang; Ma, Hongxia; Jin, Guangfu; Xu, Jianfeng; Wang, Xinru; Zhou, Zuomin; Liu, Jiayin; Zhang, Xuejun; Conrad, Don; Hu, Zhibin; Sha, Jiahao.

In: Human molecular genetics, Vol. 24, No. 19, ddv257, 01.01.2015, p. 5628-5636.

Research output: Contribution to journalArticle

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, D, Hu, Z & Sha, J 2015, 'Low-frequency germline variants across 6p22.2-6p21.33 are associated with non-obstructive azoospermia in Han Chinese men', Human molecular genetics, vol. 24, no. 19, ddv257, pp. 5628-5636. https://doi.org/10.1093/hmg/ddv257
Ni, Bixian ; Lin, Yuan ; Sun, Liangdan ; Zhu, Meng ; Li, Zheng ; Wang, Hui ; Yu, Jun ; Guo, Xuejiang ; Zuo, Xianbo ; Dong, Jing ; Xia, Yankai ; Wen, Yang ; Wu, Hao ; Li, Honggang ; Zhu, Yong ; Ping, Ping ; Chen, Xiangfeng ; Dai, Juncheng ; Jiang, Yue ; Xu, Peng ; Du, Qiang ; Yao, Bing ; Weng, Ning ; Lu, Hui ; Wang, Zhuqing ; Zhu, Xiaobin ; Yang, Xiaoyu ; Xiong, Chenliang ; Ma, Hongxia ; Jin, Guangfu ; Xu, Jianfeng ; Wang, Xinru ; Zhou, Zuomin ; Liu, Jiayin ; Zhang, Xuejun ; Conrad, Don ; Hu, Zhibin ; Sha, Jiahao. / Low-frequency germline variants across 6p22.2-6p21.33 are associated with non-obstructive azoospermia in Han Chinese men. In: Human molecular genetics. 2015 ; Vol. 24, No. 19. pp. 5628-5636.
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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.",
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T1 - Low-frequency germline variants across 6p22.2-6p21.33 are associated with non-obstructive azoospermia in Han Chinese men

AU - Ni, Bixian

AU - Lin, Yuan

AU - Sun, Liangdan

AU - Zhu, Meng

AU - Li, Zheng

AU - Wang, Hui

AU - Yu, Jun

AU - Guo, Xuejiang

AU - Zuo, Xianbo

AU - Dong, Jing

AU - Xia, Yankai

AU - Wen, Yang

AU - Wu, Hao

AU - Li, Honggang

AU - Zhu, Yong

AU - Ping, Ping

AU - Chen, Xiangfeng

AU - Dai, Juncheng

AU - Jiang, Yue

AU - Xu, Peng

AU - Du, Qiang

AU - Yao, Bing

AU - Weng, Ning

AU - Lu, Hui

AU - Wang, Zhuqing

AU - Zhu, Xiaobin

AU - Yang, Xiaoyu

AU - Xiong, Chenliang

AU - Ma, Hongxia

AU - Jin, Guangfu

AU - Xu, Jianfeng

AU - Wang, Xinru

AU - Zhou, Zuomin

AU - Liu, Jiayin

AU - Zhang, Xuejun

AU - Conrad, Don

AU - Hu, Zhibin

AU - Sha, Jiahao

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

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