A genome-wide association study in Chinese men identifies three risk loci for non-obstructive azoospermia

Hu, Zhibin; Xia, Yankai; Guo, Xuejiang; Dai, Juncheng; Li, Honggang; Hu, Haiquan; Jiang, Yue; Lu, Feng; Wu, Yibo; Yang, Xiaoyu; Li, Huizhang; Yao, Bing; Lu, Chuncheng; Xiong, Chenliang; Li, Zheng; Gui, Yaoting; Liu, Jiayin; Zhou, Zuomin; Shen, Hongbing; Wang, Xinru; Sha, Jiahao

doi:10.1038/ng.1040

Cited by 136 publications

(137 citation statements)

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“…We identified three well-replicated susceptibility loci (rs12097821 at 1p13.3 for PRMT6, rs2477686 at 1p36.32 for PEX10 and rs10842262 at 12p12.1 for SOX5) 7 .…”

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confidence: 96%

“…We recently conducted a multistage genome-wide association study (GWAS) of NOA in Han Chinese based on genotyping 587,347 single nucleotide polymorphisms (SNPs) in 981 NOA cases and 1,657 controls with a two-stage validation using 1,946 NOA cases and 4,077 controls 7 . We identified three well-replicated susceptibility loci (rs12097821 at 1p13.3 for PRMT6, rs2477686 at 1p36.32 for PEX10 and rs10842262 at 12p12.1 for SOX5) 7 .…”

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confidence: 99%

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Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men

et al. 2014

Nat Commun

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Male factor infertility affects one-sixth of couples worldwide, and non-obstructive azoospermia (NOA) is one of the most severe forms. Our previous genome-wide association study (GWAS) identified three susceptibility loci for NOA in Han Chinese men. Here we test promising associations in an extended three-stage validation using 3,608 NOA cases and 5,909 controls to identify additional risk loci. We find strong evidence of three NOA susceptibility loci (Po5.0 Â 10 À 8 ) at 6p21.32 (rs7194, P ¼ 3.76 Â 10 À 19 ), 10q25.3 (rs7099208, P ¼ 6.41 Â 10 À 14 ) and 6p12.2 (rs13206743, P ¼ 3.69 Â 10 À 8 ), as well as one locus approaching genome-wide significance at 1q42.13 (rs3000811, P ¼ 7.26 Â 10 À 8 ). In addition, we investigate the phenotypic effect of the related gene (gek, orthologous to CDC42BPA) at 1q42.13 on male fertility using a Drosophila model. These results advance our understanding of the genetic susceptibility to NOA and provide insights into its pathogenic mechanism.

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“…We identified three well-replicated susceptibility loci (rs12097821 at 1p13.3 for PRMT6, rs2477686 at 1p36.32 for PEX10 and rs10842262 at 12p12.1 for SOX5) 7 .…”

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confidence: 96%

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confidence: 99%

Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men

et al. 2014

Nat Commun

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“…With the advance of maintaining the ground state of human naive stem cells equivalent to mouse ESCs [29], it is possible that the repaired human PSCs could further differentiate into functional haploid cells using a similar germ cell differentiation protocol in mouse. In addition, an infertile male patient may harbor multiple SNP mutations, of which phenotypes could be difficult to correct [30]. With the aid of genetic analysis, we can identify the critical mutations and correct them using gene editing tools like the TALEN or CRISPR/Cas system to rescue the male infertility.…”

Section: Discussionmentioning

confidence: 99%

Generation of fertile offspring from Kitw/Kitwv mice through differentiation of gene corrected nuclear transfer embryonic stem cells

et al. 2015

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Genetic mutations could cause sperm deficiency, leading to male infertility. Without functional gametes in the testes, patients cannot produce progeny even with assisted reproduction technologies such as in vitro fertilization. It has been a major challenge to restore the fertility of gamete-deficient patients due to genetic mutations. In this study, using a Kit w /Kit wv mouse model, we investigated the feasibility of generating functional sperms from gamete-deficient mice by combining the reprogramming and gene correcting technologies. We derived embryonic stem cells from cloned embryos (ntESCs) that were created by nuclear transfer of Kit w /Kit wv somatic cells. Then we generated gene-corrected ntESCs using TALEN-mediated gene editing. The repaired ntESCs could further differentiate into primordial germ cell-like cells (PGCLCs) in vitro. RFP-labeled PGCLCs from the repaired ntESCs could produce functional sperms in mouse testes. In addition, by co-transplantation with EGFP-labeled testis somatic cells into the testes where spermatogenesis has been chemically damaged or by transplantation into Kit w /Kit wv infertile testes, non-labeled PGCLCs could also produce haploid gametes, supporting full-term mouse development. Our study explores a new path to rescue male infertility caused by genetic mutations.

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“…HSF2, belonging to the family of heat‐shock transcription factors (HSFs), plays a key role in regulating normal spermatogenesis in mice 40. At least two splice forms, HSF2a and HSF2b, were identified for HSF2 and the Hsf2a gene was expressed predominantly in the mouse testis 41.…”

Section: Culprit Genes That Have Been Identified In Autosomesmentioning

confidence: 99%

Human male infertility and its genetic causes

Miyamoto

Minase

Shin

et al. 2017

Reprod Medicine & Biology

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BackgroundInfertility affects about 15% of couples who wish to have children and half of these cases are associated with male factors. Genetic causes of azoospermia include chromosomal abnormalities, Y chromosome microdeletions, and specific mutations/deletions of several Y chromosome genes. Many researchers have analyzed genes in the AZF region on the Y chromosome; however, in 2003 the SYCP3 gene on chromosome 12 (12q23) was identified as causing azoospermia by meiotic arrest through a point mutation.MethodsWe mainly describe the SYCP3 and PLK4 genes that we have studied in our laboratory, and add comments on other genes associated with human male infertility.ResultsUp to now, The 17 genes causing male infertility by their mutation have been reported in human.ConclusionsInfertility caused by nonobstructive azoospermia (NOA) is very important in the field of assisted reproductive technology. Even with the aid of chromosomal analysis, ultrasonography of the testis, and detailed endocrinology, only MD‐TESE can confirm the presence of immature spermatozoa in the testes. We strongly hope that these studies help clinics avoid ineffective MD‐TESE procedures.

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A genome-wide association study in Chinese men identifies three risk loci for non-obstructive azoospermia

Cited by 136 publications

References 43 publications

Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men

Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men

Generation of fertile offspring from Kitw/Kitwv mice through differentiation of gene corrected nuclear transfer embryonic stem cells

Human male infertility and its genetic causes

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