Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility
Cerván-Martín M, Tüttelmann F, Lopes AM, Bossini-Castillo L, Rivera-Egea R, Garrido N, Lujan S, Romeu G, Santos-Ribeiro S, Castilla JA, Carmen Gonzalvo M, Clavero A, Maldonado V, Vicente FJ, González-Muñoz S, Guzmán-Jiménez A, Burgos M, Jiménez R, Pacheco A, González C, Gómez S, Amorós D, Aguilar J, Quintana F, Calhaz-Jorge C, Aguiar A, Nunes J, Sousa S, Pereira I, Pinto MG, Correia S, Sánchez-Curbelo J, López-Rodrigo O, Martín J, Pereira-Caetano I, Marques PI, Carvalho F, Barros A, Gromoll J, Bassas L, Seixas S, Gonçalves J, Larriba S, Kliesch S, Palomino-Morales RJ, Carmona FD., 15.11.2022
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.
Cerván-Martín M, Tüttelmann F, Lopes AM, Bossini-Castillo L, Rivera-Egea R, Garrido N, Lujan S, Romeu G, Santos-Ribeiro S, Castilla JA, Carmen Gonzalvo M, Clavero A, Maldonado V, Vicente FJ, González-Muñoz S, Guzmán-Jiménez A, Burgos M, Jiménez R, Pacheco A, González C, Gómez S, Amorós D, Aguilar J, Quintana F, Calhaz-Jorge C, Aguiar A, Nunes J, Sousa S, Pereira I, Pinto MG, Correia S, Sánchez-Curbelo J, López-Rodrigo O, Martín J, Pereira-Caetano I, Marques PI, Carvalho F, Barros A, Gromoll J, Bassas L, Seixas S, Gonçalves J, Larriba S, Kliesch S, Palomino-Morales RJ, Carmona FD. Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility. Commun Biol. 2022 Nov 10;5(1):1220. doi: 10.1038/s42003-022-04192-0. PMID: 36357561; PMCID: PMC9649734.
Publication: https://www.nature.com/articles/s42003-022-04192-0
Disclaimer
The publication Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility by Cerván-Martín M, Tüttelmann F, Lopes AM, Bossini-Castillo L, Rivera-Egea R, Garrido N, Lujan S, Romeu G, Santos-Ribeiro S, Castilla JA, Carmen Gonzalvo M, Clavero A, Maldonado V, Vicente FJ, González-Muñoz S, Guzmán-Jiménez A, Burgos M, Jiménez R, Pacheco A, González C, Gómez S, Amorós D, Aguilar J, Quintana F, Calhaz-Jorge C, Aguiar A, Nunes J, Sousa S, Pereira I, Pinto MG, Correia S, Sánchez-Curbelo J, López-Rodrigo O, Martín J, Pereira-Caetano I, Marques PI, Carvalho F, Barros A, Gromoll J, Bassas L, Seixas S, Gonçalves J, Larriba S, Kliesch S, Palomino-Morales RJ, Carmona FD. is published under an open access license: https://creativecommons.org/licenses/by/4.0/. Permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Curation by the MFGA team Relevant data sets presented in the publication have been identified. If possible, annotations (title, general information, conditions, processed tissue types and processed cell types) have been added based on information from the publication. Data tables and images that provide a good overview on the publication's findings on the data set have been extracted from the publication and/or supplement. If not stated otherwise, images are depicted with title and description exactly as in the publication. Tables have been adjusted to the MFGA table format. Conducted adjustments are explained in the detailed view of the tables. However, titles and descriptions have been adopted from the publication.
Data set 1: Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility
Genome: Genome-wide Association Study
Species
| Species |
|---|
| Human |
Cell Types
| Cell ontology | Maturity | Description | Species | Replicates | Cells per replicate |
|---|---|---|---|---|---|
| CL_0000216: Sertoli cell | A supporting cell projecting inward from the basement membrane of seminiferous tubules. They surround and nourish the developing male germ cells and secrete androgen binding protein. Their tight junctions with the spermatogonia and spermatocytes provide a blood-testis barrier. | Human | |||
| CL_0000081: blood cell | A cell found predominately in the blood. |
Images
Figure 1. Manhattan plot representation of the logistic regression test of the MHC region accordingly with Sertoli cell-only phenotype.
a Unconditioned test of the MHC region. b Results of the MHC region after conditioning on HLA-DRβ1 Ser13. The −log10 of the combined logistic regression test P-values are plotted against their physical chromosomal position. A red/blue colour gradient was used to represent the effect size of each analysed variant (red for risk and blue for protection). The red line represents the genome-wide level of significance (P < E−08).
Licensed under: https://creativecommons.org/licenses/by/4.0/
Figure 2. Manhattan plot representation of the logistic regression test for the VKR1 region accordingly with Sertoli cell-only phenotype.
Data for the Iberian discovery cohort (a), the German replication cohort (b), and the combined cohort (c) are shown. The −log10 of the P-values from the logistic regression tests and the inverse variance method are plotted against their physical chromosomal position. A red/blue colour gradient was used to represent the effect size of each analysed variant (red for risk and blue for protection). The red line represents the genome-wide level of significance (P < 5E−08).
Licensed under: https://creativecommons.org/licenses/by/4.0/
Figure 3. GARFIELD functional enrichment analysis of the GWAS results accordingly with Sertoli cell-only phenotype.
The radial axis represents the enrichment (OR) for each of the analysed cell types that are sorted by tissue along the outside edge of the plot. Boxes forming the edge are coloured by tissue. Enrichment is calculated for the GWAS P-value threshold P < 1E−05. Dots in the inner ring of the outer circle denote significant GARFIELD enrichment after multiple-testing correction for the number of effective annotations and are coloured with respect to the tissue cell type tested (font size of tissue labels reflects the number of cell types from that tissue).
Licensed under: https://creativecommons.org/licenses/by/4.0/