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Hu Z.,Nanjing Medical University | Li Z.,Shanghai JiaoTong University | Yu J.,Nanjing Medical University | Tong C.,Zhejiang University | And 39 more authors.
Nature Communications | Year: 2014

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 (P<5.0 × 10-8) at 6p21.32 (rs7194, P=3.76 × 10 -19), 10q25.3 (rs7099208, P=6.41 × 10 â ̂'14) and 6p12.2 (rs13206743, P=3.69 × 10 â ̂'8), as well as one locus approaching genome-wide significance at 1q42.13 (rs3000811, P=7.26 × 10-8). 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. © 2014 Macmillan Publishers Limited.

Ni B.,State Key Laboratory of Reproductive Medicine | Ni B.,Collaborative Innovation Center For Cancer Personalized Medicine | Lin Y.,State Key Laboratory of Reproductive Medicine | Lin Y.,Collaborative Innovation Center For Cancer Personalized Medicine | And 44 more authors.
Human Molecular Genetics | Year: 2015

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. © The Author 2015. Published by Oxford University Press. All rights reserved.

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