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

Abstract

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.

Figure 1.

Manhattan plot of exome-wide association analyses for NOA. Exome-wide association results for NOA in Han Chinese men. The association results (–log₁₀(P) values, y-axis) are plotted against genomic position (x-axis by chromosome and chromosomal position of NCBI build 37). The green horizontal line represents P = 1.0 × 10⁻⁴.

Figure 2.

Regional association plots with lead variants indicated by a purple diamond at 6p21.33 (A, B) and 6p22.2 (C). The association of an individual variant is plotted as –log₁₀ P against chromosomal position. y-Axis shows the recombination rate estimated from 1000 Genomes Project CHB and JPT data.

Figure 2.

Regional association plots with lead variants indicated by a purple diamond at 6p21.33 (A, B) and 6p22.2 (C). The association of an individual variant is plotted as –log₁₀ P against chromosomal position. y-Axis shows the recombination rate estimated from 1000 Genomes Project CHB and JPT data.