Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility
Miriam Cerván‐Martín, Frank Tüttelmann, Alexandra M. Lopes, Lara Bossini‐Castillo, Rocío Rivera‐Egea, Nicolás Garrido, Saturnino Luján, G. Romeu Magraner, Samuel Santos‐Ribeiro, José Antonio Castilla, M. Carmen Gonzálvo, Ana Clavero, Vicente Maldonado, Francisco Javier Vicente, Sara González‐Muñoz, Andrea Guzmán‐Jiménez, Miguel Burgos, Rafael Jiménez, Alberto Pacheco, Cristina González, Susana Gómez, David Amorós, Jesús S. Aguilar–Ruiz, Fernando Quintana, Carlos Calhaz–Jorge, Ana Aguiar, Joaquim Nunes, Sandra Maria Zákia Lian Sousa, Isabel Pereira, Maria Graça Pinto, Sónia Vladimira Correia, Josvany Sánchez‐Curbelo, Olga López‐Rodrigo, Javier Martı́n, Iris Pereira‐Caetano, Patrícia Marques, Filipa Carvalho, Alberto Barros, Jörg Gromoll, Lluís Bassas, Susana Seixas, João Gonçalves, Sara Larriba, Sabine Kliesch, Rogelio Palomino‐Morales, F. David Carmona
Abstract
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.