Genome-Wide Association Screening Determines Peripheral Players in Male Fertility Maintenance
Deciphering the functional relationships of genes resulting from genome-wide screens for polymorphisms that are associated with phenotypic variations can be challenging. However, given the common association with certain phenotypes, a functional link should exist. We have tested this prediction in n...
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/1/524 |
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| author | Thomas Greither Hermann M. Behre Holger Herlyn |
| author_facet | Thomas Greither Hermann M. Behre Holger Herlyn |
| author_sort | Thomas Greither |
| collection | DOAJ |
| description | Deciphering the functional relationships of genes resulting from genome-wide screens for polymorphisms that are associated with phenotypic variations can be challenging. However, given the common association with certain phenotypes, a functional link should exist. We have tested this prediction in newly sequenced exomes of altogether 100 men representing different states of fertility. Fertile subjects presented with normal semen parameters and had naturally fathered offspring. In contrast, infertile probands were involuntarily childless and had reduced sperm quantity and quality. Genome-wide association study (GWAS) linked twelve non-synonymous single-nucleotide polymorphisms (SNPs) to fertility variation between both cohorts. The SNPs localized to nine genes for which previous evidence is in line with a role in male fertility maintenance: <i>ANAPC1</i>, <i>CES1</i>, <i>FAM131C</i>, <i>HLA-DRB1</i>, <i>KMT2C</i>, <i>NOMO1</i>, <i>SAA1</i>, <i>SRGAP2</i>, and <i>SUSD2</i>. Most of the SNPs residing in these genes imply amino acid exchanges that should only moderately affect protein functionality. In addition, proteins encoded by genes from present GWAS occupied peripheral positions in a protein–protein interaction network, the backbone of which consisted of genes listed in the Online Mendelian Inheritance in Man (OMIM) database for their implication in male infertility. Suggestive of an indirect impact on male fertility, the genes focused were indeed linked to each other, albeit mediated by other interactants. Thus, the chances of identifying a central player in male infertility by GWAS could be limited in general. Furthermore, the SNPs determined and the genes containing these might prove to have potential as biomarkers in the diagnosis of male fertility. |
| first_indexed | 2024-03-11T09:59:27Z |
| format | Article |
| id | doaj.art-ff52f4b568294984896437ca0d20dd01 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:59:27Z |
| publishDate | 2022-12-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ff52f4b568294984896437ca0d20dd012023-11-16T15:34:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124152410.3390/ijms24010524Genome-Wide Association Screening Determines Peripheral Players in Male Fertility MaintenanceThomas Greither0Hermann M. Behre1Holger Herlyn2Center for Reproductive Medicine and Andrology, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyCenter for Reproductive Medicine and Andrology, Martin Luther University Halle-Wittenberg, 06120 Halle, GermanyAnthropology, Institute of Organismic and Molecular Evolution (iomE), Johannes Gutenberg University Mainz, 55099 Mainz, GermanyDeciphering the functional relationships of genes resulting from genome-wide screens for polymorphisms that are associated with phenotypic variations can be challenging. However, given the common association with certain phenotypes, a functional link should exist. We have tested this prediction in newly sequenced exomes of altogether 100 men representing different states of fertility. Fertile subjects presented with normal semen parameters and had naturally fathered offspring. In contrast, infertile probands were involuntarily childless and had reduced sperm quantity and quality. Genome-wide association study (GWAS) linked twelve non-synonymous single-nucleotide polymorphisms (SNPs) to fertility variation between both cohorts. The SNPs localized to nine genes for which previous evidence is in line with a role in male fertility maintenance: <i>ANAPC1</i>, <i>CES1</i>, <i>FAM131C</i>, <i>HLA-DRB1</i>, <i>KMT2C</i>, <i>NOMO1</i>, <i>SAA1</i>, <i>SRGAP2</i>, and <i>SUSD2</i>. Most of the SNPs residing in these genes imply amino acid exchanges that should only moderately affect protein functionality. In addition, proteins encoded by genes from present GWAS occupied peripheral positions in a protein–protein interaction network, the backbone of which consisted of genes listed in the Online Mendelian Inheritance in Man (OMIM) database for their implication in male infertility. Suggestive of an indirect impact on male fertility, the genes focused were indeed linked to each other, albeit mediated by other interactants. Thus, the chances of identifying a central player in male infertility by GWAS could be limited in general. Furthermore, the SNPs determined and the genes containing these might prove to have potential as biomarkers in the diagnosis of male fertility.https://www.mdpi.com/1422-0067/24/1/524male infertilitydisorderpolymorphismgenome-wide association studyspermatogenesisspermiogenesis |
| spellingShingle | Thomas Greither Hermann M. Behre Holger Herlyn Genome-Wide Association Screening Determines Peripheral Players in Male Fertility Maintenance International Journal of Molecular Sciences male infertility disorder polymorphism genome-wide association study spermatogenesis spermiogenesis |
| title | Genome-Wide Association Screening Determines Peripheral Players in Male Fertility Maintenance |
| title_full | Genome-Wide Association Screening Determines Peripheral Players in Male Fertility Maintenance |
| title_fullStr | Genome-Wide Association Screening Determines Peripheral Players in Male Fertility Maintenance |
| title_full_unstemmed | Genome-Wide Association Screening Determines Peripheral Players in Male Fertility Maintenance |
| title_short | Genome-Wide Association Screening Determines Peripheral Players in Male Fertility Maintenance |
| title_sort | genome wide association screening determines peripheral players in male fertility maintenance |
| topic | male infertility disorder polymorphism genome-wide association study spermatogenesis spermiogenesis |
| url | https://www.mdpi.com/1422-0067/24/1/524 |
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