Trans-ethnic GWAS meta-analysis of idiopathic spermatogenic failure highlights the immune-mediated nature of Sertoli cell-only syndrome

Abstract

Non-obstructive azoospermia, a severe form of male infertility caused by spermatogenic failure (SPGF), has a largely unknown genetic basis across ancestries. To our knowledge, this is the first trans-ethnic meta-analysis of genome-wide association studies on SPGF, involving 2255 men with idiopathic SPGF and 3608 controls from European and Asian populations. Using logistic regression and inverse variance methods, we identify two significant genetic associations with Sertoli cell-only (SCO) syndrome, the most extreme SPGF phenotype. The G allele of rs34915133, in the major histocompatibility complex class II region, significantly increases SCO risk (P = 5.25E-10, OR = 1.57), supporting a potential immune-related cause. Additionally, the rs10842262 variant in the SOX5 gene region is also a genetic marker of SCO (P = 5.29E-09, OR = 0.72), highlighting the key role of this gene in the male reproductive function. Our findings reveal shared genetic factors in male infertility across ancestries and provide insights into the molecular mechanisms underlying SCO.

Fig. 1. Manhattan plot representations of the three trans-ethnic meta-analyses conducted between the two European and the Asian genome-wide association studies of male infertility due to spermatogenic failure (SPGF).

The inverse variance meta-analysis was performed by combining the results of the “NOA vs controls” comparison from Asians with those of the “SPGF vs controls” (A), “non-obstructive azoospermia (NOA) vs controls” (B), and “Sertoli cell-only syndrome (SCO) vs controls” (C) comparisons from Europeans. The red line represents the genome-wide level of significance (P-value < 5E−08).

Fig. 2. Enrichment of functional annotations of the human genome for the Sertoli cell-only (SCO)-associated polymorphisms rs34915133 and rs10842262 (highlighted in red) as well as their proxies.

The different functional features are represented with specific colors, with color grade correlating with the probability of functional impact for each tested variant (darker colors indicate higher probability). This figure summarized the information provided in Supplementary Table 2. CADD combined annotation dependent depletion score, ChIP-seq proteins bound from chromatin immunoprecipitation flowing by sequencing experiments in the testis (using ENCODE data), eQTL expression quantitative trait locus effects in the testis, GRCh38 genome reference consortium human build 38, sQTL splicing quantitative trait locus effects in the testis, TFBS transcription factor binding sites modifications related to transcription factors involved in spermatogenesis based on protein weight matrix data.

Fig. 3. Schematic representation of the study design.

The figure illustrates the distribution of individuals included in each meta-analysis. NOA non-obstructive azoospermia, SCO Sertoli cell-only, SPGF spermatogenic failure.