Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility

• Published in: Communications biology Vol. 5; no. 1; p. 1220
• Main Authors: Cerván-Martín, Miriam, Tüttelmann, Frank, Lopes, Alexandra M., Bossini-Castillo, Lara, Rivera-Egea, Rocío, Garrido, Nicolás, Lujan, Saturnino, Romeu, Gema, Santos-Ribeiro, Samuel, Castilla, José A., Carmen Gonzalvo, M., Clavero, Ana, Maldonado, Vicente, Vicente, F. Javier, González-Muñoz, Sara, Guzmán-Jiménez, Andrea, Burgos, Miguel, Jiménez, Rafael, Pacheco, Alberto, González, Cristina, Gómez, Susana, Amorós, David, Aguilar, Jesus, Quintana, Fernando, Calhaz-Jorge, Carlos, Aguiar, Ana, Nunes, Joaquim, Sousa, Sandra, Pereira, Isabel, Pinto, Maria Graça, Correia, Sónia, Sánchez-Curbelo, Josvany, López-Rodrigo, Olga, Martín, Javier, Pereira-Caetano, Iris, Marques, Patricia I., Carvalho, Filipa, Barros, Alberto, Gromoll, Jörg, Bassas, Lluís, Seixas, Susana, Gonçalves, João, Larriba, Sara, Kliesch, Sabine, Palomino-Morales, Rogelio J., Carmona, F. David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/22; 45/43; 631/208/205/2138; 692/699/2732/1577; Alleles; Biology; Biomedical and Life Sciences; Drb1 protein; Genetic analysis; Genetic diversity; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotype & phenotype; Histocompatibility antigen HLA; Humans; Infertility; Infertility, Male - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Life Sciences; Major histocompatibility complex; Male; Phenotypes; Population studies; Protein kinase; Protein Serine-Threonine Kinases; Sertoli Cells - metabolism; Spermatogenesis; Spermatogenesis - genetics
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-04192-0

We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DRβ1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition. A GWAS in a large case-control cohort of European ancestry identifies two genomic regions, the MHC class II gene HLA-DRB1 and an upstream locus of VRK1, that are associated with the most severe phenotype of spermatogenic failure.