Mechanism of pleiotropic SNP involved in reproductive phenotypes
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PROVIDER: PRJEB70890 | ENA |
REPOSITORIES: ENA
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Project description:A common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis
| PRJNA1072980 | ENA
Project description:The common human single nucleotide polymorphism rs3820282 is associated with multiple phenotypes ranging from gestational length to likelihood of endometriosis and ovarian cancer and can thus serve as a paradigm for a highly pleiotropic genetic variant. Pleiotropy makes it challenging to assign specific causal roles to particular genetic variants. Deleterious mutations in multifunctional genes may cause either the co-occurrence of multiple disorders in the same individuals (i.e., syndromes), or be repeatedly associated with a variety of disorders in a population. Moreover, the adverse effects can be in combination with advantages in other traits, maintaining high frequencies of deleterious alleles in the population. To reveal the causal role of this specific SNP, we investigated the molecular mechanisms affected by rs3820282 in mice. We have shown previously that rs3820282 introduces a high affinity estrogen receptor 1 binding site at the Wnt4 locus. Here we introduced this nucleotide substitution into the homologous site of the mouse genome by CRISPR/Cas 9 and show that this change causes a specific upregulation of Wnt4 transcription in the endometrial stromal cells (but not that of CDC42, also located close to rs3820282) during the preovulatory estrogen peak in late proestrus. Transcriptomic analysis of the whole uterus reveals broad systemic effects on uterine gene expression, including downregulation of proliferation and induction of many progesterone-regulated pro-implantation genes. The effect on proliferation is limited to the luminal epithelium, whereas other effects involve the uterine stromal compartment. We suggest that in the uterus, these changes could contribute to increased permissiveness to embryo invasion. Yet in other estrogen-responsive tissues, the same changes potentially lead to decreased resistance to invasion by cancer cells and endometriotic foci. A single molecular effect of rs3820282 on Wnt4 expression may thus underlie the various associated phenotypic effects.
2024-02-21 | GSE254989 | GEO
Project description:Plakophilin-2 (PKP2) is a component of the desmosome complex and known for its role in cell-cell adhesion. Recently, alterations in the Pkp2 gene have been associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy (ACM or ARVC), Brugada syndrome (BrS), and idiopathic ventricular fibrillation to name the most relevant. However, the assessment of pathogenicity regarding the genetic variations associated with Pkp2 is still a challenging task: the gene has a positive Residual Variation Intolerance Score and the potential deleterious role of several of its variants has been disputed. Limitations in facilitating interpretation and annotations of these variants are seen in the lack of segregation and clinical data in the control population of reference. In this review, we will provide a summary of all the currently available genetic information related to the Pkp2 gene, including different phenotypes, ClinVar annotations and data from large control database. Our goal is to provide a literature review that could help clinicians and geneticists in interpreting the role of Pkp2 variants in the context of heritable sudden death syndromes. Limitations of current algorithms and data repositories will be discussed.
| S-EPMC6305316 | biostudies-literature
Project description:Background. Endometriosis is a common, complex disorder which is underrecognized and subject to prolonged delays in diagnosis. It is accompanied by significant changes in the eutopic endometrial lining. Methods . We have undertaken the first single cell RNA-sequencing (scRNA-Seq) comparison of endometrial tissues in freshly collected menstrual effluent (ME) from 33 subjects, including confirmed endometriosis patients (cases) and controls as well as symptomatic subjects (who have chronic symptoms of endometriosis but have not been diagnosed). Results . We identify a unique subcluster of proliferating uterine natural killer (uNK) cells in ME-tissues from controls that is almost absent from endometriosis cases, along with a striking reduction of total uNK cells in the ME of cases (p<10 -16 ). In addition, an IGFBP1+ decidualized subset of endometrial stromal cells are abundant in the shed endometrium of controls when compared to cases (p<10 -16 ) confirming findings of compromised decidualization of cultured stromal cells from cases. By contrast, endometrial stromal cells from cases are enriched in cells expressing pro-inflammatory and senescent phenotypes. An enrichment of B cells in the cases (p=5.8 x 10 -6 ) raises the possibility that some may have chronic endometritis, a disorder which predisposes to endometriosis. Conclusions . We propose that characterization of endometrial tissues in ME will provide an effective screening tool for identifying endometriosis in patients with chronic symptoms suggestive of this disorder. This constitutes a major advance, since delayed diagnosis for many years is a major clinical problem in the evaluation of these patients. Comprehensive analysis of ME is expected to lead to new diagnostic and therapeutic approaches to endometriosis and other associated reproductive disorders such as female infertility.
2022-09-21 | GSE203191 | GEO
Project description:Discovering pleiotropic loci is important to understand the biological basis of seemingly distinct phenotypes. Most methods for assessing pleiotropy only test for the overall association between genetic variants and multiple phenotypes. To determine which specific traits are pleiotropic, we evaluate via simulation and application three different strategies. The first is model selection techniques based on the inverse regression of genotype on phenotypes. The second is a subset-based meta analysis ASSET [Bhattacharjee et al., ], which provides an optimal subset of nonnull traits. And the third is a modified Benjamini-Hochberg (B-H) procedure of controlling the expected false discovery rate [Benjamini and Hochberg, ] in the framework of phenome-wide association study. From our simulations we see that an inverse regression-based approach MultiPhen [O'Reilly et al., ] is more powerful than ASSET for detecting overall pleiotropic association, except for when all the phenotypes are associated and have genetic effects in the same direction. For determining which specific traits are pleiotropic, the modified B-H procedure performs consistently better than the other two methods. The inverse regression-based selection methods perform competitively with the modified B-H procedure only when the phenotypes are weakly correlated. The efficiency of ASSET is observed to lie below and in between the efficiency of the other two methods when the traits are weakly and strongly correlated, respectively. In our application to a large GWAS, we find that the modified B-H procedure also performs well, indicating that this may be an optimal approach for determining the traits underlying a pleiotropic signal.
| S-EPMC4929010 | biostudies-literature
Project description:The study profiles endometrial samples from donors in reproductive age with and without endometriosis collected during natural cycles. Samples where profiled with Visium Spatial transcriptomics using 10x technology (v1 3').
2024-05-13 | E-MTAB-14058 | biostudies-arrayexpress
Project description:Endometriosis is a common gynecological disease that affects 10-20% of women in child-bearing age. It is defined by the presence of endometrial tissues outside the uterus. The causes remain elusive, but the endometrium of these patients differs profoundly from that of disease-free subjects. During pregnancy, the maternal-fetal interface is built onto decidualized endometrium. We investigated whether this interface is normal when the subjects suffer of endometriosis and showed remarkly properties of eutopic endometrium from endometriosis-affected women to spontaneously develop endometriotic-like lesions within direct contact to non-uterine tissues.
2014-11-10 | GSE57831 | GEO
Project description:Endometriosis is a common gyncological disease that affects 10-20% of women in child-bearing age. It is defined by the presence of endometrial tissues outside the uterus. The causes remain elusive, but the endometrium of these patients differs profoundly from that of disease-free subjects. During pregnancy, the maternal-fetal interface is built onto decidualized endometrium. We investigated whether this interface is normal when the subjects suffer of endometriosis and showed remarkly properties of eutopic endometrium from endometriosis-affected women to spontaneously develop endometriotic-like lesions within direct contact to non-uterine tissues.
2014-11-10 | GSE57733 | GEO
Project description:BackgroundAdvances in genotyping and phenotyping techniques have enabled the acquisition of a great amount of data. Consequently, there is an interest in multivariate statistical analyses that identify genomic regions likely to contain causal mutations affecting multiple traits (i.e., pleiotropy). As the demand for multivariate analyses increases, it is imperative that optimal tools are available to assess their performance. To facilitate the testing and validation of these multivariate approaches, we developed simplePHENOTYPES, an R/CRAN package that simulates pleiotropy, partial pleiotropy, and spurious pleiotropy in a wide range of genetic architectures, including additive, dominance and epistatic models.ResultsWe illustrate simplePHENOTYPES' ability to simulate thousands of phenotypes in less than one minute. We then provide two vignettes illustrating how to simulate sets of correlated traits in simplePHENOTYPES. Finally, we demonstrate the use of results from simplePHENOTYPES in a standard GWAS software, as well as the equivalence of simulated phenotypes from simplePHENOTYPES and other packages with similar capabilities.ConclusionssimplePHENOTYPES is a R/CRAN package that makes it possible to simulate multiple traits controlled by loci with varying degrees of pleiotropy. Its ability to interface with both commonly-used marker data formats and downstream quantitative genetics software and packages should facilitate a rigorous assessment of both existing and emerging statistical GWAS and GS approaches. simplePHENOTYPES is also available at https://github.com/samuelbfernandes/simplePHENOTYPES .
| S-EPMC7603745 | biostudies-literature
Project description:Semen samples from men after a short ejaculatory abstinence show improved sperm quality and result in increased pregnancy rates, but the underlying mechanisms remain unclear. Herein, we report that ejaculates from short (1–3 hours) compared with long (3–7 days) periods of abstinence showed increases in motile sperm count, sperm vitality, normal sperm morphology, acrosome reaction capacity, total antioxidant capacity, sperm mitochondrial membrane potential, high DNA stainability, and a decrease in the sperm DNA fragmentation index (P < 0.05). Sperm proteomic analysis showed 322 differentially expressed proteins (minimal fold change of ±1.5 or greater and P < 0.05), with 224 up-regulated and 98 down-regulated. These differentially expressed proteins are profoundly involved in specific cellular processes, such as motility and capacitation, oxidative stress, and metabolism. Interestingly, protein trimethyllysine modification was increased, and butyryllysine, propionyllysine, and malonyllysine modifications were decreased in ejaculates from a short versus long abstinence (P < 0.05). Finally, the rates of implantation, clinical pregnancy, and live births from in vitro fertilization treatments were significantly increased in semen samples after a short abstinence. Our study provides preliminary mechanistic insights into improved sperm quality and pregnancy outcomes associated with spermatozoa retrieved after a short ejaculatory abstinence
2019-02-22 | PXD010695 | Pride