Excess of rare variants in genes that are key epigenetic regulators of spermatogenesis in the patients with non-obstructive azoospermia.
Non-obstructive azoospermia (NOA), a severe form of male infertility, is often suspected to be linked to currently undefined genetic abnormalities. To explore the genetic basis of this condition, we successfully sequenced ~650 infertility-related genes in 757 NOA patients and 709 fertile males. We evaluated the contributions of rare variants to the etiology of NOA by identifying individual genes showing nominal associations and testing the genetic burden of a given biological process as a whole. We found a significant excess of rare, non-silent variants in genes that are key epigenetic regulators of spermatogenesis, such as BRWD1, DNMT1, DNMT3B, RNF17, UBR2, USP1 and USP26, in NOA patients (P = 5.5 × 10(-7)), corresponding to a carrier frequency of 22.5% of patients and 13.7% of controls (P = 1.4 × 10(-5)). An accumulation of low-frequency variants was also identified in additional epigenetic genes (BRDT and MTHFR). Our study suggested the potential associations of genetic defects in genes that are epigenetic regulators with spermatogenic failure in human.
1] Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China [2] Shenzhen Key Laboratory of Genitourinary Cancer, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China [3] National-Regional Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Zesong
Z
Li
1] Shenzhen Key Laboratory of Genitourinary Cancer, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China [2] National-Regional Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Yi
Y
Huang
Family Planning Research Institute/The Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Honggang
H
Li
BGI-Shenzhen, Shenzhen 518083, China.
Jingchu
J
Hu
BGI-Shenzhen, Shenzhen 518083, China.
Xiao
X
Liu
BGI-Shenzhen, Shenzhen 518083, China.
Tao
T
Jiang
BGI-Shenzhen, Shenzhen 518083, China.
Guangqing
G
Sun
1] Shenzhen Key Laboratory of Genitourinary Cancer, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China [2] National-Regional Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Aifa
A
Tang
1] Shenzhen Key Laboratory of Genitourinary Cancer, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China [2] National-Regional Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Xiaojuan
X
Sun
The Center of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen 518036, China.
Weiping
W
Qian
Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Urology Hospital, Shenzhen 518045, China.
Yong
Y
Zeng
Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
Jun
J
Xie
BGI-Shenzhen, Shenzhen 518083, China.
Wei
W
Zhao
BGI-Shenzhen, Shenzhen 518083, China.
Yu
Y
Xu
BGI-Shenzhen, Shenzhen 518083, China.
Tingting
T
He
BGI-Shenzhen, Shenzhen 518083, China.
Chengliang
C
Dong
The Center of Reproductive Medicine, Peking University Shenzhen Hospital, Shenzhen 518036, China.
Qunlong
Q
Liu
1] Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China [2] Shenzhen Key Laboratory of Genitourinary Cancer, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China [3] National-Regional Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Lisha
L
Mou
1] Shenzhen Key Laboratory of Genitourinary Cancer, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China [2] National-Regional Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Jingxiao
J
Lu
Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
Zheguang
Z
Lin
1] Shenzhen Key Laboratory of Genitourinary Cancer, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China [2] National-Regional Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Song
S
Wu
BGI-Shenzhen, Shenzhen 518083, China.
Shengjie
S
Gao
BGI-Shenzhen, Shenzhen 518083, China.
Guangwu
G
Guo
BGI-Shenzhen, Shenzhen 518083, China.
Qiang
Q
Feng
BGI-Shenzhen, Shenzhen 518083, China.
Yingrui
Y
Li
BGI-Shenzhen, Shenzhen 518083, China.
Xiuqing
X
Zhang
BGI-Shenzhen, Shenzhen 518083, China.
Jun
J
Wang
BGI-Shenzhen, Shenzhen 518083, China.
Huanming
H
Yang
BGI-Shenzhen, Shenzhen 518083, China.
Jian
J
Wang
Family Planning Research Institute/The Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Chengliang
C
Xiong
1] Shenzhen Key Laboratory of Genitourinary Cancer, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China [2] National-Regional Engineering Laboratory for Clinical Application of Cancer Genomics, Shenzhen Second People's Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Zhiming
Z
Cai
Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen 518036, China.
Yaoting
Y
Gui
D000483:Alleles; D053713:Azoospermia / Q000235:genetics*; D044127:Epigenesis, Genetic; D057890:Epigenomics; D020869:Gene Expression Profiling / Q000379:methods; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D005819:Genetic Markers; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D008297:Male; D013091:Spermatogenesis / Q000235:genetics*
D005819:Genetic Markers