Comprehensive pathway-based analysis identifies associations of BCL2, GNAO1 and CHD2 with non-obstructive azoospermia risk.

STUDY QUESTION

Do genetic variants in known canonical pathways that have been widely suggested to affect spermatogenesis confer susceptibility to non-obstructive azoospermia (NOA)?

SUMMARY ANSWER

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.

WHAT IS KNOWN ALREADY

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.

STUDY DESIGN, SIZE, DURATION: We conducted a two-stage association study containing 1653 NOA cases and 2329 controls to investigate the susceptibility markers for NOA.

PARTICIPANTS/MATERIALS, SETTING, 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.

MAIN RESULTS AND THE ROLE OF CHANCE

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).

LIMITATIONS, REASONS FOR CAUTION: Our analysis of genes in the pathways studied was not exhaustive.

WIDER IMPLICATIONS OF THE FINDINGS

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.