title: Comprehensive pathway-based analysis identifies associations of BCL2, GNAO1 and CHD2 with non-obstructive azoospermia risk.
abstract: OBJECTIVE
  Do genetic variants in known canonical pathways that have been widely suggested to affect spermatogenesis confer susceptibility to non-obstructive azoospermia (NOA)?
  
  
  CONCLUSIONS
  Rs1406714 in CHD2, rs2126986 in GNAO1 and rs7226979 in BCL2 were associated with NOA in Han Chinese men at a significant level after multiple testing corrections.
  
  
  BACKGROUND
  Previous genome-wide association studies (GWASs) have identified three loci for NOA, whereas less attention has been given to those markers that did not exceed the genome-wide significance threshold.
  
  
  METHODS
  We conducted a two-stage association study containing 1653 NOA cases and 2329 controls to investigate the susceptibility markers for NOA.
  
  
  METHODS
  Imputation and pathway-based approaches can be applied to identify additional causal makers with small effects on NOA. We performed a candidate pathway-based association study using imputed-genotyping data for 24 238 single nucleotide polymorphisms estimated from NOA GWAS. Remarkably, 40 markers were associated with NOA in both imputation analysis and NOA GWAS (Stage 1) after linkage disequilibrium analysis and selected for validation (Stage 2) in another population.
  
  
  RESULTS
  Based on the literature, genes from 11 biological pathways known or hypothesized to be important in spermatogenesis were selected. Combined analysis using directly genotyped data for Stages 1 and 2 revealed that rs1406714 in CHD2 was associated with decreased risk of NOA [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.68-0.89, Pmeta = 1.7E-04], whereas rs2126986 in GNAO1 and rs7226979 in BCL2 were both risk makers for NOA (rs2126986: OR = 1.28, 95% CI = 1.15-1.41, Pmeta = 2.3E-06; rs7226979: OR = 1.21, 95% CI = 1.11-1.33, Pmeta = 4.5E-05).
  
  
  CONCLUSIONS
  Our analysis of genes in the pathways studied was not exhaustive.
  
  
  CONCLUSIONS
  Our study opens new avenues for the identification of other novel causal markers that are related to NOA. It will also provide a new paradigm for understanding the etiology of male infertility and contribute to the development of targeted therapies.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 818 East Tianyuan Road, Nanjing 211166, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Qin
authors.forename: Juan
authors.initials: J
authors.lastname: Ji
authors.forename: Guizhen
authors.initials: G
authors.lastname: Du
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Juncheng
authors.initials: J
authors.lastname: Dai
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Hu
authors.forename: Jiahao
authors.initials: J
authors.lastname: Sha
authors.forename: Bo
authors.initials: B
authors.lastname: Hang
authors.forename: Chuncheng
authors.initials: C
authors.lastname: Lu
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
mesh_terms: D053713:Azoospermia / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*
chemical_list: C575189:CHD2 protein, human; D004268:DNA-Binding Proteins; C584143:GNAO1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: SNP; male infertility; non-obstructive azoospermia; pathway-based analysis