title: Pathogenic variants screening in five non-obstructive azoospermia-associated genes.
abstract: Non-obstructive azoospermia (NOA) is one of the most severe forms of male infertility and a recent, genome-wide association study (GWAS) has identified four risk loci associated with NOA. However, a large portion of the heritability of NOA has not been well explained by GWAS. By hypothesizing that rare, low-frequency and common genetic variants might point toward a causal relation between candidate genes and NOA, we performed a two-stage study including deep exon sequencing in 96 NOA cases and 96 healthy controls and a replication study in a larger population containing 522 NOA cases and 484 healthy controls. In the solexa sequencing stage, a total of two rare mutations (chr20. 1902132 and chr20. 1902301 in SIRPA), four common mutations (rs1048055 and rs2281807 in SIRPG, rs11046992 and rs146039840 in SOX5) were identified by using next generation sequencing (NGS). In the validation stage, subjects in the NOA group had a significantly decreased frequency of the heterozygous GA genotype in SIRPA (4.23%, 22 out of 520) than that in the control group (8.60%, 41 out of 477) [odds ratios (OR) 0.47, 95% confidence intervals (CI) 0.28-0.80] (P = 6.00 × 10(-3)). The rs1048055 in SIRPG was associated with a significantly increased risk of spermatogenic impairment, compared with the CC genotype (OR 3.93, 95% CI 1.59-9.70) (P = 3.00 × 10(-3)). Our study provides evidence of independent NOA risk alleles driven by variants in the protein-coding sequence of two of the genes (SIRPA and SIRPG) discovered by GWAS. Further investigation in larger populations and functional characterizations are needed to validate our findings.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Chuncheng
authors.initials: C
authors.lastname: Lu
authors.forename: Miaofei
authors.initials: M
authors.lastname: Xu
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Qin
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Shoulin
authors.initials: S
authors.lastname: Wang
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.forename: Jiahao
authors.initials: J
authors.lastname: Sha
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
mesh_terms: D000328:Adult; D000483:Alleles; D000943:Antigens, Differentiation / Q000235:genetics*; D053713:Azoospermia / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002890:Chromosomes, Human, Pair 20; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic / Q000235:genetics*; D012306:Risk; D055755:SOXD Transcription Factors / Q000235:genetics*; D013091:Spermatogenesis / Q000235:genetics
chemical_list: D000943:Antigens, Differentiation; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; C490691:SIRPG protein, human; C490301:SOX5 protein, human; D055755:SOXD Transcription Factors
keywords: genetic variants; non-obstructive azoospermia; spermatogenic impairment