Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia

Funding Information: This work was supported by the Spanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and Innovation (PID 2020-120157RB-I00) and the Andalusian Government through the research projects of “Plan Andaluz de Investigacion, Desarrollo e Innovacion (PAIDI 2020)” (ref. PY20_00212) and “Programa Operativo FEDER 2020” (ref. B-CTS-584-UGR20). LB-C was supported by the Spanish Ministry of Science and Innovation through the “Juan de la Cierva Incorporacion” program (Grant ref. IJC 2018-038026-I, funded by MCIN/AEI/10.13039/501100011033), which includes FEDER funds. AG-J was funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro” (grant ref. FPU20/02926). IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds (projects PEstC/SAU/LA0003/2013 and POCI-01-0145-FEDER-007274). PM is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the Programa Operacional do Capital Humano. ToxOmics—Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, Lisbon, is also partially supported by FCT (UID/BIM/00009/2016 and UIDB/00009/2020). SL received support from Instituto de Salud Carlos III (grant: DTS18/00101], co-funded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe-), and from “Generalitat de Catalunya” (grant 2017SGR191). SL is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). This article is related to the Ph.D. Doctoral Thesis of AG-J. Publisher Copyright: Copyright © 2022 Guzmán-Jiménez, González-Muñoz, Cerván-Martín, Rivera-Egea, Garrido, Luján, Santos-Ribeiro, Castilla, Gonzalvo, Clavero, Vicente, Maldonado, Villegas-Salmerón, Burgos, Jiménez, Pinto, Pereira, Nunes, Sánchez-Curbelo, López-Rodrigo, Pereira-Caetano, Marques, Carvalho, Barros, Bassas, Seixas, Gonçalves, Lopes, Larriba, Palomino-Morales, Carmona, Bossini-Castillo, IVIRMA Group and Lisbon Clinical Group.Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33–02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.publishersversionpublishe

Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia

Lisbon clinical group co-authors and IVIRMA group co-authors Ana Aguiar, (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal); Carlos Calhaz-Jorge, (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal); Joaquim Nunes, (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal); Sandra Sousa (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal), and Sónia Correia (Centro de Medicina Reprodutiva, Maternidade Alfredo da Costa, Centro Hospitalar Lisboa Central, Lisboa, Portugal); Maria Graça Pinto(Centro de Medicina Reprodutiva, Maternidade Alfredo da Costa, Centro Hospitalar Lisboa Central, Lisboa, Portugal). Alberto Pacheco, (IVIRMA Madrid, Spain); Cristina González, (IVIRMA Sevilla, Spain); Susana Gómez, (IVIRMA Lisboa, Portugal); David Amorós, (IVIRMA Barcelona, Spain); Jesús Aguilar, (IVIRMA Vigo, Spain); Fernando Quintana, (IVIRMA Bilbao, Spain).Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33–02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.This work was supported by the Spanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and Innovation (PID 2020-120157RB-I00) and the Andalusian Government through the research projects of “Plan Andaluz de Investigacion, Desarrollo e Innovacion (PAIDI 2020)” (ref. PY20_00212) and “Programa Operativo FEDER 2020” (ref. B-CTS-584-UGR20). LB-C was supported by the Spanish Ministry of Science and Innovation through the “Juan de la Cierva Incorporacion” program (Grant ref. IJC 2018-038026- I, funded by MCIN/AEI/10.13039/501100011033), which includes FEDER funds. AG-J was funded by MCIN/AEI/ 10.13039/501100011033 and FSE “El FSE invierte en tu futuro” (grant ref. FPU20/02926). IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds (projects PEstC/SAU/LA0003/2013 and POCI-01-0145-FEDER-007274). PM is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the Programa Operacional do Capital Humano. ToxOmics—Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, Lisbon, is also partially supported by FCT (UID/BIM/00009/2016 and UIDB/00009/2020). SL received support from Instituto de Salud Carlos III (grant: DTS18/00101], co-funded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe-), and from “Generalitat de Catalunya” (grant 2017SGR191). SL is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). This article is related to the Ph.D. Doctoral Thesis of AG-J.info:eu-repo/semantics/publishedVersio

Evaluation of male fertility-associated loci in a european population of patients with severe spermatogenic impairment

Funding: This work was supported by the Spanish Ministry of Economy and Competitiveness through the Spanish State Plan for Scientific and Technical Research and Innovation (ref. SAF2016-78722-R), the “Ramón y Cajal” program (ref. RYC-2014-16458), and the “Juan de la Cierva Incorporación” program (ref. IJC2018-038026-I), which include FEDER funds. SLa received support from the Spanish Ministry of Science and Innovation (grants FIS-ISCIII DTS18/00101, co-funded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe-), and from Generalitat de Catalunya (grant 2017SGR191). AG-J was recipient of a grant from the “Plan Propio” program of the University of Granada (“Becas de Iniciación a la Investigación para estudiantes de Grado”, conv.2019). SLa is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). JG was partially funded by FCT/MCTES, through national funds attributed to Center for Toxicogenomics and Human Health—ToxOmics (UIDB/00009/2020). PIM is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the Programa Operacional do Capital Humano. AML is funded by the Portuguese Government through FCT (IF/01262/2014). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274).Infertility is a growing concern in developed societies. Two extreme phenotypes of male infertility are non-obstructive azoospermia (NOA) and severe oligospermia (SO), which are characterized by severe spermatogenic failure (SpF). We designed a genetic association study comprising 725 Iberian infertile men as a consequence of SpF and 1058 unaffected controls to evaluate whether five single-nucleotide polymorphisms (SNPs), previously associated with reduced fertility in Hutterites, are also involved in the genetic susceptibility to idiopathic SpF and specific clinical entities. A significant difference in the allele frequencies of USP8-rs7174015 was observed under the recessive model between the NOA group and both the control group (p = 0.0226, OR = 1.33) and the SO group (p = 0.0048, OR = 1.78). Other genetic associations for EPSTI1-rs12870438 and PSAT1-rs7867029 with SO and between TUSC1-rs10966811 and testicular sperm extraction (TESE) success in the context of NOA were observed. In silico analysis of functional annotations demonstrated cis-eQTL effects of such SNPs likely due to the modification of binding motif sites for relevant transcription factors of the spermatogenic process. The findings reported here shed light on the molecular mechanisms leading to severe phenotypes of idiopathic male infertility, and may help to better understand the contribution of the common genetic variation to the development of these conditions.publishersversionpublishe

Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia

Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag singlenucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33–02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.Spanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and InnovationAndalusian Government PID 2020-120157RB-I 00Ministry of Science and Innovation, Spain (MICINN) Spanish Government PY20_00212 B-CTS-584-UGR20 MCIN/AEI IJC 2018-03802 6-IEuropean Commission FPU20/02926Portuguese Foundation for Science and TechnologyEuropean Social Fund (ESF)National FundsPortuguese Foundation for Science and Technology European Commission PEstC/SAU/LA0003/2013 POCI-01-0145-FEDER-007274 Portuguese State Budget of the Ministry for Science, Technology and High Education SFRH/BPD/120777/201 6 UID/BIM/00 009/2016 UIDB/00009/20 20European Social Fund (ESF)ToxOmics-Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, LisbonInstituto de Salud Carlos III European Commission FEDER funds/European Regional Development Fund (ERDF) DTS18/001 01SNS-DptGeneralitat de CatalunyaSNS-Dpt. Salut Generalitat de Catalunya 2017SGR191 Exp. CES09/02

Table1_Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia.XLSX

Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF.Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants.Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33–02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis.Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.</p