A comprehensive study of common and rare genetic variants in spermatogenesis-related loci identifies new risk factors for idiopathic severe spermatogenic failure

STUDY QUESTION: Can genome-wide genotyping data be analysed using a hypothesis-driven approach to enhance the understanding of the genetic basis of severe spermatogenic failure (SPGF) in male infertility? SUMMARY ANSWER: Our findings revealed a significant association between SPGF and the SHOC1 gene...

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Autores: Guzmán-Jiménez, Andrea|||0000-0002-2091-0568, González-Muñoz, Sara, Cerván-Martín, Miriam|||0000-0001-6033-0587, Garrido, Nicolás|||0000-0001-8271-5218, Castilla, José Antonio|||0000-0003-2185-565X, Gonzálvo, María Carmen, Clavero, Ana, Molina, Marta, Luján, Saturnino|||0000-0002-5005-3325, Santos-Ribeiro, Samuel|||0000-0003-2476-7858, Vilches, Miguel Angel|||0000-0002-5533-437X, Espuch, Andrea, Maldonado, Vicente|||0000-0003-4456-7191, Galiano-Gutiérrez, Noelia, Santamaría-López, Esther, González-Ravina, Cristina, Quintana-Ferraz, Fernando, Gómez, Susana, Amorós, David, Martínez-Granados, Luis, Ortega-González, Yanira, Burgos, Miguel|||0000-0003-4446-9313, Pereira-Caetano, Iris, Bulbul, Ozgur, Castellano, Stefano, Romano, Massimo, Albani, Elena, Bassas, Lluís|||0000-0002-3473-3611, Seixas, Susana|||0000-0002-7035-7422, Gonçalves, João|||0000-0001-9359-8774, Lopes, Alexandra M.|||0000-0003-3539-2318, Larriba, Sara|||0000-0003-4579-5452, Palomino-Morales, Rogelio J.|||0000-0003-3507-343X, Carmona, F. David|||0000-0002-1427-7639, Bossini-Castillo, Lara|||0000-0002-5471-5824
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:310171
Acceso en línea:https://ddd.uab.cat/record/310171
https://dx.doi.org/urn:doi:10.1093/hropen/hoae069
Access Level:acceso abierto
Palabra clave:Genetics
Idiopathic spermatogenic failure
Male infertility
Monogenic mutations
Polygenic susceptibility
Spermatogenesis
Descripción
Sumario:STUDY QUESTION: Can genome-wide genotyping data be analysed using a hypothesis-driven approach to enhance the understanding of the genetic basis of severe spermatogenic failure (SPGF) in male infertility? SUMMARY ANSWER: Our findings revealed a significant association between SPGF and the SHOC1 gene and identified three novel genes (PCSK4, AP3B1, and DLK1) along with 32 potentially pathogenic rare variants in 30 genes that contribute to this condition. WHAT IS KNOWN ALREADY: SPGF is a major cause of male infertility, often with an unknown aetiology. SPGF can be due to either multifactorial causes, including both common genetic variants in multiple genes and environmental factors, or highly damaging rare variants. Next-generation sequencing methods are useful for identifying rare mutations that explain monogenic forms of SPGF. Genome-wide association studies (GWASs) have become essential approaches for deciphering the intricate genetic landscape of complex diseases, offering a cost-effective and rapid means to genotype millions of genetic variants. Novel methods have demonstrated that GWAS datasets can be used to infer rare coding variants that are causal for male infertility phenotypes. However, this approach has not been previously applied to characterize the genetic component of a whole case-control cohort. STUDY DESIGN, SIZE, DURATION: We employed a hypothesis-driven approach focusing on all genetic variation identified, using a GWAS platform and subsequent genotype imputation, encompassing over 20 million polymorphisms and a total of 1571 SPGF patients and 2431 controls. Both common (minor allele frequency, MAF.

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