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Changes in environmental exposures over decades may influence the genetic architecture of severe spermatogenic failure

2024-03-01Journal article Open access
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datacite.subject.fosCiências Médicas
dc.contributor.authorCerván-Martín, Miriam
dc.contributor.authorGonzález-Muñoz, Sara
dc.contributor.authorGuzmán-Jiménez, Andrea
dc.contributor.authorHigueras-Serrano, Inmaculada
dc.contributor.authorCastilla, José A.
dc.contributor.authorGarrido, Nicolás
dc.contributor.authorLuján, Saturnino
dc.contributor.authorBassas, Lluís
dc.contributor.authorSeixas, Susana
dc.contributor.authorGonçalves, João
dc.contributor.authorLopes, Alexandra M
dc.contributor.authorLarriba, Sara
dc.contributor.authorPalomino-Morales, Rogelio J.
dc.contributor.authorBossini-Castillo, Lara
dc.contributor.authorCarmona, F. David
dc.date.accessioned2025-02-17T16:16:32Z
dc.date.available2025-02-17T16:16:32Z
dc.date.issued2024-03-01
dc.description.abstractStudy question: Do the genetic determinants of idiopathic severe spermatogenic failure (SPGF) differ between generations? Summary answer: Our data support that the genetic component of idiopathic SPGF is impacted by dynamic changes in environmental exposures over decades. What is known already: The idiopathic form of SPGF has a multifactorial etiology wherein an interaction between genetic, epigenetic, and environmental factors leads to the disease onset and progression. At the genetic level, genome-wide association studies (GWASs) allow the analysis of millions of genetic variants across the genome in a hypothesis-free manner, as a valuable tool for identifying susceptibility risk loci. However, little is known about the specific role of non-genetic factors and their influence on the genetic determinants in this type of conditions. Study design, size, duration: Case-control genetic association analyses were performed including a total of 912 SPGF cases and 1360 unaffected controls. Participants/materials, setting, methods: All participants had European ancestry (Iberian and German). SPGF cases were diagnosed during the last decade either with idiopathic non-obstructive azoospermia (n = 547) or with idiopathic non-obstructive oligozoospermia (n = 365). Case-control genetic association analyses were performed by logistic regression models considering the generation as a covariate and by in silico functional characterization of the susceptibility genomic regions. Main results and the role of chance: This analysis revealed 13 novel genetic association signals with SPGF, with eight of them being independent. The observed associations were mostly explained by the interaction between each lead variant and the age-group. Additionally, we established links between these loci and diverse non-genetic factors, such as toxic or dietary habits, respiratory disorders, and autoimmune diseases, which might potentially influence the genetic architecture of idiopathic SPGF. Large scale data: GWAS data are available from the authors upon reasonable request. Limitations, reasons for caution: Additional independent studies involving large cohorts in ethnically diverse populations are warranted to confirm our findings. Wider implications of the findings: Overall, this study proposes an innovative strategy to achieve a more precise understanding of conditions such as SPGF by considering the interactions between a variable exposome through different generations and genetic predisposition to complex diseases.eng
dc.description.sponsorshipThis work was supported by the "Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020)" (ref. PY20_00212, P20_00583), the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. PID2020-120157RB-I00 funded by MCIN/AEI/10.13039/501100011033), and the 'Proyectos I+D+i del Programa Operativo FEDER 2020' (ref. B-CTS-584-UGR20). ToxOmics-Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, is also partially supported by the Portuguese Foundation for Science and Technology (Projects: UIDB/00009/2020; UIDP/00009/2020).
dc.identifier.citationHum Reprod. 2024 Mar 1;39(3):612-622. doi: 10.1093/humrep/deae007
dc.identifier.doi10.1093/humrep/deae007
dc.identifier.issn1460-2350
dc.identifier.pmid38305414
dc.identifier.urihttp://hdl.handle.net/10400.18/10355
dc.language.isoeng
dc.peerreviewedyes
dc.publisherOxford University Press
dc.relationCentre for Toxicogenomics and Human Health
dc.relationCentre for Toxicogenomics and Human Health
dc.relation.hasversionhttps://academic.oup.com/humrep/article/39/3/612/7596397
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectGWAS
dc.subjectComplex Trait
dc.subjectExposome
dc.subjectGenetics
dc.subjectMale Infertility
dc.subjectSpermatogenic Failure
dc.subjectDoenças Genéticas
dc.titleChanges in environmental exposures over decades may influence the genetic architecture of severe spermatogenic failureeng
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCentre for Toxicogenomics and Human Health
oaire.awardTitleCentre for Toxicogenomics and Human Health
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00009%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F00009%2F2020/PT
oaire.citation.endPage622
oaire.citation.issue3
oaire.citation.startPage612
oaire.citation.titleHuman Reproduction
oaire.citation.volume39
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
relation.isProjectOfPublicationa438b9d1-8a6a-4c90-a13b-7ccf34071451
relation.isProjectOfPublication8836ec79-2300-487a-97ad-75e98cfabcfa
relation.isProjectOfPublication.latestForDiscoverya438b9d1-8a6a-4c90-a13b-7ccf34071451

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