Calcium homeostasis and endometriosis: A Mendelian randomization study
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ABSTRACT:
SUBMITTER: Deng Z
PROVIDER: S-EPMC11336440 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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Project description:Observational studies have investigated the impact of calcium homeostasis on psychiatric disorders; however, the causality of associations is yet to be established. Bidirectional Mendelian randomization (MR) analysis of calcium homeostasis hormones was conducted on nine psychiatric disorders. Calcium, serum 25-hydroxyvitamin D levels (25OHD), parathyroid hormone, and fibroblast growth factor 23 are the major calcium homeostasis hormones. The causality was evaluated by the inverse variance weighted method (IVW) and the MR Steiger test, while Cochran's Q test, the MR-Egger intercept test, funnel plot, and the leave-one-out method were used for sensitivity analyses. Bonferroni correction was used to determine the causative association features (p < 6.94 × 10-4). Schizophrenia (SCZ) was significantly associated with decreased 25OHD concentrations with an estimated effect of -0.0164 (Prandom-effect IVW = 2.39 × 10-7). In the Multivariable MR (MVMR) analysis adjusting for potentially confounding traits including body mass index, obesity, mineral supplements (calcium, fish oil, and vitamin D) and outdoor time (winter and summer), the relationship between SCZ and 25OHD remained. The genetically predicted autism spectrum disorder and bipolar disorder were also nominally associated with decreased 25OHD. This study provided evidence for a causal effect of psychiatric disorders on calcium homeostasis. The clinical monitoring of 25OHD levels in patients with psychiatric disorders is beneficial.
| S-EPMC10535008 | biostudies-literature
Project description:BackgroundEndometriosis, a prevalent chronic condition, afflicts approximately 10% of women in their reproductive years. Emerging evidence implicates immune cells in the pathogenesis of endometriosis, particularly in angiogenesis, tissue proliferation, and lesion invasion. This investigation employs two-sample Mendelian Randomization (MR) to dissect the bidirectional causal relationships between immune cell profiles and endometriosis.MethodsWe leveraged publicly available genome-wide association study (GWAS) data to elucidate the causal interplay between immune cell traits and endometriosis. Utilizing GWAS summary statistics ranging from accession numbers GCST90001391 to GCST90002121 and endometriosis data from the FinnGen study GWAS (8,288 endometriosis cases and 68,969 controls), we adopted stringent criteria for instrumental variable selection. We applied MR-Egger, weighted median, inverse variance weighted (IVW), and weighted mode methods to derive causal estimates. To address potential heterogeneity and pleiotropy, Cochran's Q test, MR-Egger intercept, and leave-one-out analyses were executed. Reverse-direction MR and bidirectional MR analyses evaluated potential reciprocal causation and the influence of endometriosis on immune cell composition.ResultsOur analysis identified five immune phenotypes inversely associated with endometriosis risk. These phenotypes comprise: a percentage of CD11c + HLA-DR + + monocytes, CD25 expression on CD39 + CD4 + T cells, elevated CD25 on CD45RA + CD4 + non-regulatory T cells, HLA-DR intensity on HLA-DR + CD8 bright (CD8br) T cells, and the proportion of naïve double-negative (CD4 - CD8- %DN) T cells. In contrast, eleven phenotypes were positively correlated with endometriosis risk, including: CD127 expression on T cells, the proportion of CD24 + CD27 + B cells within lymphocytes, CD25 expression on CD28 + CD4 + T cells, CD28 expression on CD39 + activated regulatory T cells (activated Tregs), the frequency of bright CD33 HLA-DR + CD14 - cells within the CD33br HLA-DR + compartment, CD45 expression on lymphocytes and natural killer (NK) cells, activation status of central memory CD8 bright (CM CD8br) T cells, CX3CR1 expression on monocytes, and the percentage of HLA-DR + NK cells within the NK cell subset. Sensitivity assessments that excluded significant heterogeneity and pleiotropy confirmed the stability of these associations, thereby reinforcing the validity of our findings.ConclusionThis study provides novel evidence of the potential causal impact of specific immune cells on the risk of developing endometriosis. These findings enhance our understanding of endometriosis pathophysiology and may inform innovative approaches for its diagnosis and management. While our findings provide novel insights, limitations such as potential horizontal pleiotropy and reliance on European ancestry data should be considered. Future research should expand to diverse populations and incorporate individual-level data to refine these findings.
| S-EPMC11515284 | biostudies-literature
Project description:BackgroundObservational studies and animal experiments had suggested a potential relationship between gut microbiota abundance and pathogenesis of endometriosis (EMs), but the relevance of this relationship remains to be clarified.MethodsWe perform a two-sample bidirectional Mendelian randomization (MR) analysis to explore whether there is a causal correlation between the abundance of the gut microbiota and EMs and the direction of causality. Genome-wide association study (GWAS) data ukb-d-N80, finn-b-N14-EM, and MiBinGen were selected. Inverse variance weighted (IVW), weighted median, and MR Egger are selected for causal inference. The Cochran Q test, Egger intercept test, and leave-one-out analysis are performed for sensitivity analyses.ResultsIn the primary outcome, we find that a higher abundance of class Negativicutes, genus Dialister, genus Enterorhabdus, genus Eubacterium xylanophilum group, genus Methanobrevibacter and order Selenomonadales predict a higher risk of EMs, and a higher abundance of genus Coprococcus and genus Senegalimassilia predict a lower risk of EMs. During verifiable outcomes, we find that a higher abundance of phylum Cyanobacteria, genus Ruminococcaceae UCG002, and genus Coprococcus 3 predict a higher risk of EMs, and a higher abundance of genus Flavonifracto, genus Bifidobacterium, and genus Rikenellaceae RC9 predict a lower risk of EMs. In primary reverse MR analysis, we find that EMs predict a lower abundance of the genus Eubacterium fissicatena group, genus Prevotella7, genus Butyricicoccus, family Lactobacillaceae, and a higher abundance of genus Ruminococcaceae UCG009. In verifiable reverse MR analysis, we find that EMs predict a lower abundance of the genus Ruminococcaceae UCG004 and a higher abundance of the genus Howardella.ConclusionOur study implies a mutual causality between gut microbiota abundance and the pathogenesis of EMs, which may provide a novel direction for EMs diagnosis, prevention, and treatment, may promote future functional or clinical analysis.
| S-EPMC11621931 | biostudies-literature
Project description:BackgroundRecent studies have shown that an imbalance in gut microbiota (GM) may not always be associated with endometriosis (EMS). To investigate this further, we conducted a two-sample Mendelian randomization study.MethodsMR analysis was performed on genome-wide association study (GWAS) summary statistics of GM and EMS. Specifically, the MiBioGen microbiota GWAS (N = 18,340) was used as exposure. The FinnGen study GWAS (8,288 EMS cases and 68,969 controls) was used as outcome. We primarily used the inverse variance weighted (IVW) method to analyze the correlation and conducted a sensitivity analysis to verify its reliability.Results(1) MR analysis: The results of the IVW method confirmed that a total of 8 GM taxa were related to the risk of EMS. Class-Melainabacteria (p = 0.036), family-Ruminococcaceae (p = 0.037), and genus-Eubacteriumruminantium (p = 0.015) had a protective effect on EMS, whereas order-Bacillales (p = 0.046), family-Prevotellaceae (p = 0.027), genus-Anaerotruncus (p = 0.025), genus-Olsenella (p = 0.036) and genus-RuminococcaceaeUCG002 (p = 0.035) could increase the risk of EMS. (2) Sensitivity analysis: Cochrane's Q test (p > 0.05), MR-Egger intercept method (p > 0.05), and leave-one-out method confirmed the robustness of MR results.ConclusionThis study performed a MR analysis on two large national databases and identified the association between 8 GM taxa and EMS. These taxa could potentially be utilized for indirectly diagnosing EMS and could lead to novel perspectives in research regarding the pathogenesis, diagnosis, and treatment of EMS.
| S-EPMC10565803 | biostudies-literature
Project description:Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12-6.38; P = 2.7 × 10(-2)). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs).
| S-EPMC4850434 | biostudies-other
Project description:Migraine affects ∼14% of the world's population, though not all predisposing causal risk factors are known. We used electronic health records, genetic co-heritability analysis, and a two-sample Mendelian Randomization (MR) design to determine if elevated serum calcium levels were associated with risk of migraine headache. Co-morbidity was evaluated using electronic health records obtained from the PennOmics database comprising >1 million patient entries. Genetic co-heritability and causality via MR was assessed using data from the International Headache Consortium (23,285 cases, 95,425 controls) and circulating serum calcium levels (39,400 subjects). We observed co-occurrence of migraine and hypercalcaemia ICD-9 diagnoses (OR = 1.58, P = 4 × 10-13), even after inclusion of additional risk factors for migraine (OR = 1.23, P = 2 × 10-3). Second, we observed co-heritability (rg = 0.191, P = 0.03) between serum calcium and migraine headache, indicating that these traits have a genetic basis in common. Finally, we found that elevation of serum calcium levels by 1 mg/dl resulting from our genetic score was associated with an increase in risk of migraine (OR = 1.80, 95% CI: 1.31-2.46, P = 2.5 × 10-4), evidence supporting a causal hypothesis. We also present multiple MR sensitivity analyses in support of this central finding. Our results provide evidence that hypercalcaemia is comorbid with migraine headache diagnoses, and that genetically elevated serum calcium over lifetime appears to increase risk for migraine. Further studies will be required to understand the biological mechanism, pathways, and clinical implication for risk management.
| S-EPMC5409060 | biostudies-literature
Project description:BackgroundThough increasing epidemiological studies have evaluated the correlation between serum calcium contents and Parkinson's disease (PD), the results are inconsistent. At present, whether there is a causal association between serum calcium content and PD remains undetermined.Objective and methodsThis study was designed to explore the relationship between increased serum calcium contents and PD risk. In this present study, a Mendelian randomization trial was carried out using a large-scale serum calcium genome-wide association study (GWAS) dataset (N = 61,079, Europeans) and a large-scale PD GWAS dataset (N = 8,477, Europeans including 4,238 PD patients and 4,239 controls). Here, a total of four Mendelian randomization methods comprising weighted median, inverse-variance weighted meta-analysis (IVW), MR-Egger, and MR-PRESSO were used.ResultsOur data concluded that genetically higher serum calcium contents were not significantly related to PD.ConclusionIn conclusion, we provided genetic evidence that there was no direct causal relationship between serum calcium contents and PD. Hence, calcium supplementation may not result in reduced PD risk.
| S-EPMC7431982 | biostudies-literature
Project description:BackgroundPrevious studies have shown observational associations between the gut microbiota and endometriosis; however, the causal nature of such associations remains unclear. This study aimed to analyze the genetic causal relationship between the two.MethodsA gut microbiome genome-wide association study conducted by the MiBioGen consortium was used as exposure data, and summary statistics of endometriosis were obtained from the FinnGen consortium R8 release data. Inverse variance weighted, MR-Egger, weighted median, weighted model, and simple model analyses were applied to examine the causal relationship, and sensitivity analyses were conducted to validate the robustness of the results.ResultsThe results showed that, out of 211 gut microbiome taxa, Clostridiales_vadin_BB60_group, Oxalobacteraceae, Desulfovibrio, Haemophilus, and Holdemania had protective effects on endometriosis, while Porphyromonadaceae and Anaerotruncus might contribute to the development of endometriosis. Heterogeneity and pleiotropy analyses confirmed the robustness of the results.ConclusionThe two-sample Mendelian randomization analysis conducted in this study identified specific intestinal flora with a causal relationship with endometriosis at the genetic level, offering new insights into the gut microbiota-mediated development mechanism of endometriosis.
| S-EPMC10687921 | biostudies-literature
Project description:ObjectivesEndometriosis (EM), a prevalent estrogen-dependent inflammatory disorder affecting women of reproductive age, is characterized by the presence of endometrial-like tissue outside the uterus, resulting in pelvic scarring, pain, and infertility. Although the pathogenesis of EM remains poorly understood, there is growing evidence suggesting the involvement of the immune system in its etiology, pathophysiology, and associated morbidities such as pain, infertility, and adverse pregnancy outcomes. While previous studies have indicated a close relationship between the immune system and EM, the specific underlying mechanism remains incompletely elucidated.MethodsThrough the utilization of publicly available genetic data, a two-sample Mendelian randomization (MR) analysis was conducted to establish an association between 731 immune cell phenotypes and EM. Comprehensive sensitivity analyses were performed to validate the robustness, heterogeneity, and potential horizontal pleiotropy of the findings.ResultsThe MR analysis revealed potential associations between 22 immune cell phenotypes and EM. Conversely, reverse MR analysis identified 11 immune phenotypes demonstrating potential associations between genetic liability in the immune phenotypes and EM.ConclusionThis study provides evidence of a potential correlation between immune cell phenotypes and EM, including the existence of reverse causation. These findings open up new avenues for investigating the underlying mechanisms of EM.
| S-EPMC11660437 | biostudies-literature
Project description:Observational studies have reported an association between gastroesophageal reflux disease (GERD) and endometriosis. We conducted a two-sample and bidirectional Mendelian randomization analysis to determine whether those associations are causal. Two-sample and bidirectional MR analyses were performed using summary statistics from the European Individual Genome-Wide Association Study (GWAS). The inverse variance weighting (IVW) method is used as the main analysis method to evaluate causality. Sensitivity analyses were performed to assess heterogeneity, horizontal versatility, and stability. The results showed no significant causal association between GERD in women with endometriosis in the UK Bank database [ratio (OR) ≈ 0, 95% adjusted interval (CI) 1.0007∼1.0044, P = 0.006] and Finn databases [ratio (OR) = 1.29, 95% adjusted interval (CI) 0.99∼1.67, P = 0.06]. However, when studying the Finn database only for endometriosis, which is confined to the uterus, a significant increase in GERD was limited to the risk of endometriosis in the uterus [ratio (OR) = 1.47, 95% adjusted interval (CI) 1.00∼2.17, P = 0.05]. Sensitivity analysis showed that the results were robust and did not detect multi efficacy or heterogeneity. Meanwhile, reverse MR analysis showed that endometriosis did not increase the risk of GERD. This MR study supports a causal relationship between GERD and an increased risk of endometriosis confined to the uterus. Therefore, patients with gastric esophageal reflux should be treated with gynecological examination to avoid and prevent the development of endometriosis.
| S-EPMC11558527 | biostudies-literature