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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.

Low-frequency germline variants across 6p22.2–6p21.33 are associated with non-obstructive azoospermia in Han Chinese men