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 Xu; Qiang 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

doi:10.1093/hmg/ddv257

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

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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.

Original language	English (US)
Pages (from-to)	5628-5636
Number of pages	9
Journal	Human molecular genetics
Volume	24
Issue number	19
DOIs	https://doi.org/10.1093/hmg/ddv257
State	Published - Oct 1 2015
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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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., ... 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, 24(19), 5628-5636. https://doi.org/10.1093/hmg/ddv257

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 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, pp. 5628-5636. https://doi.org/10.1093/hmg/ddv257

@article{d27b5179b0f94a1ca2f6e11dcc936ac3,

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.",

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

year = "2015",

month = oct,

day = "1",

doi = "10.1093/hmg/ddv257",

language = "English (US)",

volume = "24",

pages = "5628--5636",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "19",

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TY - JOUR

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, Donald F.

AU - Hu, Zhibin

AU - Sha, Jiahao

PY - 2015/10/1

Y1 - 2015/10/1

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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U2 - 10.1093/hmg/ddv257

DO - 10.1093/hmg/ddv257

M3 - Article

C2 - 26199320

AN - SCOPUS:84943755037

SN - 0964-6906

VL - 24

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JO - Human molecular genetics

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ER -

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

Abstract

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