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

Hu, Zhibin; Li, Zheng; Yu, Jun; Tong, Chao; Lin, Yuan; Guo, Xuejiang; Lu, Feng; Dong, Jing; Xia, Yankai; Wen, Yiping; Wu, Hao; Li, Honggang; Zhu, Yong; Ping, Ping; Chen, Xiang-Feng; Dai, Juncheng; Jiang, Yue; Pan, Shandong; Xu, Peng; Luo, Kun; Du, Qiyun; Yao, Bing; Ming, Liang; Gui, Yaoting; Weng, Ning; Lü, Hui; Wang, Zhuqing; Zhang, Fengbin; Zhu, Xiaobin; Yang, Xiaoyu; Zhang, Zhou; Zhao, Han; Xiong, Chenliang; Ma, Hongxia; Jin, Guangfu; Chen, Feng; Xu, Jianfeng; Wang, Xinru; Zhou, Zuomin; Chen, Zi‐Jiang; Liu, Jiayin; Shen, Hongbing; Sha, Jiahao

doi:10.1038/ncomms4857

Cited by 64 publications

(74 citation statements)

References 29 publications

(34 reference statements)

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“…6035 and 5118 exhibited CNVs on 6p21.32. Hu et al (2014) investigated 3608 NOA cases and 5909 controls to identify additional risk loci, and found that 6p21.32 as one of the strong evidence of the NOA susceptibility loci. The CNVs on 6p21.32 involved OMIM genes, HLA-DRB1 and HLA-DQA1, which belong to human leukocyte antigen (HLA) class II genes.…”

Section: Discussionmentioning

confidence: 99%

Copy number variations in spermatogenic failure patients with chromosomal abnormalities and unexplained azoospermia

Dong¹,

Pan²,

Wang³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Male infertility is mostly caused by spermatogenic failure. Currently, routine genetic analyses of unexplained azoospermia or oligozoospermia are limited to the investigation of Y chromosomal microdeletions and chromosome karyotype analyses. The aim of this study was to find spermatogenic failure genes in patients with chromosomal abnormalities and unexplained azoospermia caused by copy number variations in order to provide a theoretical basis for further research. Spermatogenic failure patients consisting of 13 males with chromosomal abnormalities and 20 with unexplained azoospermia were enrolled. The subjects underwent high-throughput genome-wide sequencing to find copy number variants (CNVs), and the results were analyzed using the Database of Genomic Variants, Online Mendelian Inheritance in Man database, and PubMed. The results showed that 16 CNVs were detected in 11 patients with chromosome abnormalities, and 26 CNVs were found in 16 males with azoospermia. Our data showed CNV-involved loci including: three times on 11p11.12 and 14q11.2 and twice on 6p21.32, 13q11, 15q11.11, 16p12.2, 16042 Y. Dong et al.

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Section: Discussionmentioning

confidence: 99%

Copy number variations in spermatogenic failure patients with chromosomal abnormalities and unexplained azoospermia

Dong¹,

Pan²,

Wang³

et al. 2015

Genet. Mol. Res.

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“…Our study has uncovered genetic causes and molecular mechanisms underlying NOA; these results will likely provide direction for the genetic testing and treatment of patients with NOA. (13,14). We report that U2A, the Drosophila homolog of human SNRPA1, is essential for male fertility.…”

Section: Significancementioning

confidence: 99%

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans

Sun

Wen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Processing of pre-mRNA into mRNA is an important regulatory mechanism in eukaryotes that is mediated by the spliceosome, a huge and dynamic ribonucleoprotein complex. Splicing defects are implicated in a spectrum of human disease, but the underlying mechanistic links remain largely unresolved. Using a genome-wide association approach, we have recently identified single nucleotide polymorphisms in humans that associate with nonobstructive azoospermia (NOA), a common cause of male infertility. Here, using genetic manipulation of corresponding candidate loci in Drosophila, we show that the spliceosome component SNRPA1/U2A is essential for male fertility. Loss of U2A in germ cells of the Drosophila testis does not affect germline stem cells, but does result in the accumulation of mitotic spermatogonia that fail to differentiate into spermatocytes and mature sperm. Lack of U2A causes insufficient splicing of mRNAs required for the transition of germ cells from proliferation to differentiation. We show that germ cellspecific disruption of other components of the major spliceosome manifests with the same phenotype, demonstrating that mRNA processing is required for the differentiation of spermatogonia. This requirement is conserved, and expression of human SNRPA1 fully restores spermatogenesis in U2A mutant flies. We further report that several missense mutations in human SNRPA1 that inhibit the assembly of the major spliceosome dominantly disrupt spermatogonial differentiation in Drosophila. Collectively, our findings uncover a conserved and specific requirement for the major spliceosome during the transition from spermatogonial proliferation to differentiation in the male testis, suggesting that spliceosome defects affecting the differentiation of human spermatogonia contribute to NOA.

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“…Furthermore, infertility is genetically heterogeneous; scores of distinct genes cause grossly identical phenotypes when mutated in mice (2,16). This likely explains why genome-wide association studies (GWAS) have not been effective even in stratified cohorts, with only two reporting significant associations with NOA in Chinese populations (11,17). Even if associations could be readily obtained, identification and validation of causative variants would remain problematic.…”

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confidence: 99%

The genetics of human infertility by functional interrogation of SNPs in mice

Singh

Schimenti

2015

Proc. Natl. Acad. Sci. U.S.A.

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Infertility is a prevalent health issue, affecting ∼15% of couples of childbearing age. Nearly one-half of idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. Traditional methods for studying inheritance, such as genome-wide association studies and linkage analyses, have been confounded by the genetic and phenotypic complexity of reproductive processes. Here we describe an association-and linkagefree approach to identify segregating infertility alleles, in which CRISPR/Cas9 genome editing is used to model putatively deleterious nonsynonymous SNPs (nsSNPs) in the mouse orthologs of fertility genes. Mice bearing "humanized" alleles of four essential meiosis genes, each predicted to be deleterious by most of the commonly used algorithms for analyzing functional SNP consequences, were examined for fertility and reproductive defects. Only a Cdk2 allele mimicking SNP rs3087335, which alters an inhibitory WEE1 protein kinase phosphorylation site, caused infertility and revealed a novel function in regulating spermatogonial stem cell maintenance. Our data indicate that segregating infertility alleles exist in human populations. Furthermore, whereas computational prediction of SNP effects is useful for identifying candidate causal mutations for diverse diseases, this study underscores the need for in vivo functional evaluation of physiological consequences. This approach can revolutionize personalized reproductive genetics by establishing a permanent reference of benign vs. infertile alleles.CRISPR/Cas9 | meiosis | spermatogenesis | cyclin | genome editing

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

Cited by 64 publications

References 29 publications

Copy number variations in spermatogenic failure patients with chromosomal abnormalities and unexplained azoospermia

Copy number variations in spermatogenic failure patients with chromosomal abnormalities and unexplained azoospermia

Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans

The genetics of human infertility by functional interrogation of SNPs in mice

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