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The Y chromosome has high genetic variability with low rates of parallel and back mutations, which make up the most informative haplotyping system. To examine whether Y chromosome haplogroups (Y-hgs) could modify the effects of autosomal variants on non-obstructive azoospermia (NOA), based on our previous genome-wide association study (GWAS), we conducted a genetic interaction analysis in GWAS subjects. Logistic regression analysis demonstrated a protective effect of Y-hg O3e *  on NOA. Then, we explored the potential interaction between Y-hg O3e *  and autosomal variants. Our results demonstrated that there was a suggestively significant interaction between Y-hg O3e *  and rs11135484 on NOA ( P  inter  = 9.89 × 10 −5 ). Bioinformatic analysis revealed that genes annotated by significant single nucleotide polymorphisms (SNPs) were mainly enriched in immunological pathways. This is the first study of interactions between Y-hgs and autosomal variants on a genome-wide scale, which addresses the missing heritability in spermatogenic impairment and sheds new light on the pathogenesis of male infertility.

Y chromosome haplogroups based genome-wide association study pinpoints revelation for interactions on non-obstructive azoospermia