Genetic Link Research Articles

The relationship between pulmonary ventilation function and bone marrow hematopoietic function: A mendelian randomization analysis

Background: In recent years, the comorbidity between respiratory and hematopoietic system diseases has emerged as a new challenge. However, the potential genetic link between the ventilatory function of the respiratory system and the hematopoietic function of the bone marrow remains unclear. In this study, we conducted a comprehensive investigation into the possible genetic connection between lung ventilatory function and bone marrow hematopoietic function. Methods: We selected two exposure factors, Forced Expiratory Volume in 1 second (FEV1) and Forced Vital Capacity (FVC), which represent pulmonary ventilation function, and two outcome indicators, Immature Fraction of Reticulocytes (IFR) and Reticulocyte Count (RC), which represent bone marrow hematopoiesis function, from published genome-wide association studies. Based on the three core assumptions of Mendelian randomization analysis, we extracted Single Nucleotide Polymorphism (SNPs) associated with FEV1 and FVC as instrumental variables for the exposure factors. We then conducted two-sample Mendelian randomization analyses using inverse variance weighted (IVW), weighted median, and MR-Egger regression methods. Lastly, we assessed the reliability of the testing results through MR-Egger, Cochran’s Q test, and the leave-one-out test. Through these steps, we aimed to explore the causal relationship between pulmonary ventilation function and the outcome of bone marrow hematopoiesis function and evaluated the reliability of the testing results using methods such as MR-Egger, Cochran’s Q test, and the leave-one-out test. Results: The IVW method revealed that a decrease in FEV1 is associated with an increase in IFR (β = −0.072, 95% CI: −0.131 to −0.014, p = 0.01), and the results from MR-Egger regression showed a similar association (β = −0.169, 95% CI: −0.342 to −0.004, p = 0.05). Furthermore, a decrease in FEV1 is associated with an increase in RC (β = −0.143, 95% CI: −0.198 to −0.087, p =4.00E-07), and MR-Egger regression yielded consistent results (β = −0.216, 95% CI: −0.381 to −0.541, p=1.07E-02). Similarly, a decrease in FVC is associated with an increase in IFR (β = −0.073, 95% CI: −0.116 to −0.031, p = 6.17E-04), and MR-Egger regression showed a similar trend (β = −0.046, 95% CI: −0.160 to −0.067, p=0.42). Additionally, a decrease in FVC is associated with an increase in RC (β = −0.173, 95% CI: −0.221 to −0.125, p = 2.33E-12), and MR-Egger regression yielded consistent results (β = −0.142, 95% CI: −0.272 to −0.012, p = 3.32E-02). The reliability tests indicated heterogeneity in the above MR analyses but no evidence of horizontal pleiotropy. Therefore, a fixed-effect model IVW was used to explore the causal relationships, which were found to be robust and reliable with no outliers or significant bias in this study. Conclusion: This study indicates that there is a negative causal relationship between pulmonary ventilation function and bone marrow hematopoietic function. A decrease in pulmonary ventilation function stimulates bone marrow hematopoiesis. However, further research is needed to elucidate this mechanism.

Genetic link between gut microbiota, immune cells, and rheumatoid arthritis: Mechanism of action of CD28 proteins

The gut microbiota serves a crucial function in modulating the immune responses of the host, as well as in managing inflammation within the body. In this particular study, the researchers sought to delve deeper into the specific mechanisms through which CD28 interacts with the gut microbiota and influences the functionality of immune cells. The study collected intestinal microbial samples from RA patients and healthy controls, analyzed microbial composition by high-throughput sequencing, and detected CD28 expression in T cells in combination with cellular immunology methods. At the same time, the effects of CD28 deletion on intestinal microbiota changes and inflammatory responses were evaluated using animal models. The findings from this study revealed a notable distinction in the gut microbiota profiles of individuals diagnosed with rheumatoid arthritis (RA) when compared to those of healthy control subjects. Specifically, the abundance of certain microbial species was observed to have a negative correlation with the expression levels of CD28, highlighting a complex interaction between the gut microbiome and the immune regulatory mechanisms involved in RA. Furthermore, experiments conducted on mice lacking CD28 demonstrated considerable alterations in their gut microbiota composition. These Cd28-deficient mice exhibited elevated levels of inflammatory markers, indicating an interplay between CD28 and the regulation of both the microbiota and the immune response.

In-situ zircon and cassiterite LA-ICP-MS geochronology and implications for granite-hosted Sn deposit models and exploration: Insights from the Cameroon Line

Abstract Tin mineralization of significant economic importance occurs across the continental portion of the Cameroon Line (CL). Tin deposits therein occur as both primary and secondary (residual and alluvial) ore. Though the temporal and, by inference, the genetic link between Sn mineralization and the host granite had long been modeled and widely accepted worldwide, in the CL, however, the age of the granite hosting cassiterite is poorly constrained, preventing a robust assessment of the temporal and genetic relationship between the Sn mineralization and its host rock. Here, we present in-situ zircon and cassiterite laser ablation inductively coupled mass spectrometry (LA-ICP-MS) U-Pb data in order not only to constrain the age of the granitic rock hosting the primary Sn ore but also to bracket the time frame of Sn mineralization, with respect to the magmatic-hydrothermal evolution of the parental magma of the host granite. Zircon from two greisen-altered, cassiterite-bearing granite samples yield overlapping and concordant ages of 64.21 ± 0.59 Ma and 65.46 ± 0.95 Ma, respectively, which are also overlapping with regional granite magmatism in the CL (ca. 65–30 Ma). On the other hand, cassiterite, which is spatially associated with the Paleocene zircon, yields Lower Eocene ages of 54.99 ± 0.35 Ma and 56.08 ± 0.46 Ma. The ca. 10 Myr time gap between zircon and cassiterite suggests that the granite is a passive host not genetically related to the Sn mineralization, which may be linked to a younger, concealed intrusion of ca. 55 Ma. This finding contrasts with the most widely accepted petrogenetic model of tin granite, according to which Sn mineralization and the host granite are cogenetic.

OA26 Atypical Multisystem Inflammation related to infection or just plain old polyarteritis nodosa?

Abstract Introduction We present the case of a 5-year-old boy with episodes of pyrexia of unknown origin associated with polyarthritis, central neuroinflammation and mucocutaneous manifestations. His skin biopsy demonstrated a nodular vasculitis which could be consistent with polyarteritis nodosa. Interestingly though, he had additional atypical rashes, ocular inflammation and evidence of acute and past streptococcal infection and his fever and CRP normalised prior to corticosteroid initiation. Case description A five-year-old British African male presented with five-week history of persistent fever, headaches, joint pain and bilateral eye pain. He was transferred to a tertiary paediatric infectious disease’s unit due to unrelenting fever with no fixed pattern, despite nine days of broad-spectrum intravenous antibiotics. He was diagnosed with neuroinflammation of uncertain aetiology, evidenced by leptomeningeal enhancement and bilateral papillitis on brain MRI. CSF microbiology and autoimmune profiles were negative. There was no evidence of primary malignancy. The fever resolved with pulsed IV methylprednisolone and the child was discharged home on a weaning regime of oral prednisolone. After stopping steroid treatment, he represented with high-grade fever, limping, anterior uveitis and new-onset non tender cutaneous lesions, plaques over eyelids and cheek and annular lesions over arms, legs and buttocks. Repeat MRI of the brain and spine showed resolution of previous neuroinflammation. Blood tests revealed raised ANA, IgG and ASOT titre, and his throat swab was positive for Group A Streptococcus. He completed 10 days of intravenous antibiotics and oral high dose ibuprofen (10 mg/kg TDS). On review by tertiary paediatric rheumatology, he was identified to have pleomorphic skin rash and subcutaneous nodules. Skin and deep tissue biopsy confirmed lobular and septal panniculitis with necrotising vasculitis, consistent with a nodular vasculitis. Treatment with high-dose steroid and mycophenolate mofetil (MMF) was initiated, but his CRP and fever had resolved prior to his first dose. He experienced improvement in systemic symptoms and arthritis; however, skin lesions persisted, with appearance of new lesions and hyperpigmentation, on reduction of steroid dose. His course was complicated by acute varicella infection, requiring oral aciclovir. Further treatment trials included topical tacrolimus and topical corticosteroids for his skin lesions. At one biopsy site, he experienced significant delay in wound healing. The genetic panel for primary immunodeficiency panel (R15) demonstrated no pathological variants. Discussion This case report highlights that, whilst the biopsy may be consistent with nodular vasculitis, such as PAN, the clinical manifestations are not perfectly aligned. Discussion within the rheumatology community would support optimal patient care. Childhood-onset Polyarteritis Nodosa (c-PAN) is a rare systemic vasculitis. Although the aetiology is unknown, associations with infections like group A streptococcus and hepatitis B suggest a postinfectious autoimmune response. There are no clear genetic links to PAN, but PAN-like vasculitis is part of reported monogenic autoinflammatory conditions. Key atypical features in this case include uveitis at presentation, nonspecific central neuroinflammation, unusual cutaneous lesion morphology, improvement of acute phase reactants before immunomodulatory treatment, and delayed biopsy wound healing. While ocular findings in PAN may include episcleritis, scleritis, keratitis, retinal vascular occlusions, and ocular ischemic syndrome, uveitis has not been reported in c-PAN. The patient also showed nonspecific inflammatory changes on initial MRI. Neurological involvement in c-PAN typically includes cerebrovascular accidents, cranial nerve palsies, and mononeuritis multiplex, with meningeal involvement being less common (reported 4% in a study of 69 children). Additionally, the patient experienced delayed wound healing following the biopsy, which is undocumented in c-PAN, but may be related to immune modulating treatment. A positive streptococcal throat swab could suggest an immune reaction as part of bacterial tonsilitis, or Acute Rheumatic Fever. However, he did not meet Jones Criteria, there was no response to prolonged antibiotics and the chronic remitting nature made these less likely. An autoinflammatory disorder, Deficiency of Adenosine Deaminase 2 (DADA2), was also considered but he had no evidence of livedo racemosa, strokes and no CECR1 mutation was identified. Our case has been discussed within a multidisciplinary team and we speculate that it could represent a previously undefined immune sensitivity within the autoimmune, autoinflammatory and immune deficiency spectrum giving an exaggerated response to infection. Key learning points • This case presents a significant diagnostic challenge due to its atypical clinical features and inconclusive extensive investigations, including immunologic testing, tissue biopsy, and genetic analysis. • While the patient’s symptoms improved with high-dose steroids and MMF, the recurrence of symptoms upon tapering steroids underscores the persistent inflammatory nature of the disease. • The detection of group A Streptococcus in the patient’s throat swab suggests a potential postinfectious autoimmune trigger, highlighting the role infections can play in the pathogenesis of vasculitis. The negative results from the R15 Primary Immunodeficiency panel suggest that more advanced genetic and immunologic testing may be beneficial. • We invite discussion on whether additional genetic or immunologic testing could optimise this patient’s care and contribute to the broader understanding of atypical vasculitis syndromes.

Novel association of LBX1 mutation with tetralogy of Fallot and hypertrophic cardiomyopathy: implications for cardiac development.

Tetralogy of Fallot (TOF) and hypertrophic cardiomyopathy (HCM) are common types of congenital heart disease with unique pathophysiologic features. Mutations in LBX1, a key regulator of muscle precursor cell migration, may disrupt these critical developmental processes, resulting in severe developmental abnormalities. This case reports on a 4-year-old girl diagnosed with both TOF and HCM. Genetic analysis revealed iUPI-F (uniparental disomy) on the entire chromosome 10, with a c.808G > A (p. Glu270Lys) pure mutation in the LBX1. This patient exhibited both TOF and HCM with mutations in the LBX1 gene, suggesting a potentially novel genetic link. This case study emphasizes the need for further studies on the function of the LBX1 gene in cardiac development and its potential impact on TOF and HCM.

Exploring genetic links between blood metabolites and gout susceptibility.

Gout, a prevalent form of inflammatory arthritis, has a complex etiology where the causal relationship between metabolites and the disease remains underexplored. This study aims to elucidate the impact of genetically determined blood metabolites on gout. Employing a two-sample bidirectional Mendelian randomization analysis, we examined the association between 1400 blood metabolites and gout. Causal associations were determined using the inverse variance weighted (IVW) method with false discovery rate (FDR) correction. Sensitivity analyses encompassed weighted models, MR-Egger, weighted median, and MR-PRESSO approaches. MR-pleiotropy and Cochran's Q statistic were utilized to evaluate potential heterogeneity and pleiotropy. Additionally, metabolic pathway analyses were conducted to pinpoint relevant pathways. Of the initial 4 serum metabolites identified, 3 known metabolites-hexanoylglutamine levels, mannose content, and the phosphate to mannose ratio-were found to be causally associated with gout, along with 55 serum metabolites identified as potential predictors of gout (PIVW < 0.05). Furthermore, we discovered 3 metabolic pathways implicated in gouty attacks. Our findings, derived from Mendelian randomization, indicate that the identified metabolites and pathways may serve as biomarkers for clinical screening and prevention of gout. Additionally, they offer novel insights into the mechanisms of the disease and potential drug targets. Key points • Conducted a comprehensive Mendelian randomization study involving 1400 blood metabolites to explore their genetic impact on gout development and progression • Identified three key metabolites-hexanoylglutamine, mannose, and the phosphate-to-mannose ratio-with causal associations to gout, highlighting their potential use as biomarkers for early detection and risk stratification • Discovered 55 additional serum metabolites as potential predictors of gout, offering new insights into the pathophysiology of the disease and identifying high-risk individuals • Revealed three novel metabolic pathways involved in gout attacks, providing new therapeutic targets for precision medicine in gout treatment.

Causal association between visceral fat and coronary artery disease: a large-scale mendelian randomization analysis

Abstract Background While increased body mass index (BMI) is an established risk factor, the residual risk associated with visceral fat, remains a concern. We aimed to perform a Mendelian randomization to explore the causal relationship between visceral fat and the risk of coronary artery disease (CAD), aiming to address gaps left by observational studies that may be influenced by confounding factors and reverse causation. Methods Leveraging large-scale genome-wide association study (GWAS) databases, we identified single-nucleotide polymorphisms (SNPs) associated with visceral fat. These genetic instruments were analyzed to infer causal relationships with CAD outcomes, drawing data from the CARDIoGRAMplusC4D consortium for CAD, and additional databases for related cardiovascular conditions. We performed a Two-sample Mendelian Randomization (MR) to test the genetic association between the visceral obesity and Coronary Artery Disease (CAD). Results The analysis encompassed data from a combined cohort exceeding 500,000 participants, revealing a significant causal relationship between increased levels of visceral fat and the risk of CAD. The observed odds ratio (OR) for CAD per standard deviation (SD) increase in visceral fat was [OR, 1.48 ] ([95% CI, 1.33-1.64]; P&amp;lt;0.001), indicating a robust association which remains independent from BMI on mediation analysis. Notably, the study's methodology ensured minimal risk of pleiotropy, reinforcing the validity of the findings. Conclusions This Mendelian randomization study provides compelling evidence of a genetic causal link between visceral fat and coronary artery disease. The findings suggest that beyond BMI, visceral fat represents a significant, independent risk factor for CAD, underscoring the importance of considering comprehensive lipid management in cardiovascular risk reduction strategies. Further research is warranted to explore potential mechanisms and therapeutic targets associated with visceral fat in the context of cardiovascular disease.

Genome-wide association study of CMR image-based aortic stiffness in 45,789 individuals identifies loci linked with cardiovascular diseases

Abstract Background The use of artificial intelligence on large-scale cardiac magnetic resonance (CMR) imaging data has enabled detailed characterisation of cardiac shape and function for use in genome-wide association studies (GWAS), leading to improved understanding of genetic aetiology of cardiovascular diseases (CVDs). Aortic stiffness is associated with increased risk of cardiovascular events in observational studies. Here, we present a novel CMR-based pressure-independent measure of aortic stiffness, identify genetic associations and explore links with CVDs. Purpose Identify genetic contributions to pressure-independent aortic stiffness and links to CVDs using large-scale GWAS analysis on the UK Biobank cohort. Methods A pre-trained neural network was used to segment CMR images of participants in the UK Biobank to quantify ascending aorta diameter, which together with contemporaneous systolic and diastolic blood pressure measurements (SBP, DBP, respectively) were used to calculate a pressure-independent measure of aortic stiffness (β0). The measurement assumes an exponential relationship between pressure and aortic diameter. We then performed a GWAS on β0 in 45,789 participants of European ancestry without CVDs. A multi-trait-based conditional &amp; joint analysis (mtCOJO) was performed to estimate genetic effects independent of SBP, DBP and aortic area. We mapped the independent lead variants associated with aortic stiffness at P &amp;lt; 5x10-8 to nearest gene, and characterised shared genetic association across CVDs using Open Targets Platform database. Results The GWAS identified 17 independent lead variants, including 6 that remained significant in the conditional analysis. Four of these lead variants, not previously reported in GWAS of other aortic traits, were located near CTD-2203A3.1, MCF2L, CFDP1 and CDH13 genes (red annotations in the Figure). MCF2L, CFDP1 and CDH13 have been associated with coronary artery disease, and CFDP1 with myocardial infarction and coronary atherosclerosis in previous studies. Conclusion A GWAS of CMR-derived aortic stiffness identified 4 loci distinct from other aortic traits that also associate with other CVDs, suggesting genetic links between aortic stiffness and CVDs. Further analyses are required to explore biological mechanisms underlying these genetic associations.Aortic Stiffness Manhattan Plot

Application of Mendelian randomization to explore the genetic association between drinking habits of different beverages and sleep disorder

IntroductionThis study aims to provide genetic evidence linking Drinking Habits of Different Beverages (DHDB) to Sleep Disorder Liability (SDL), potentially informing clinical treatments to improve lifestyle factors.Material and methodsA two-sample Mendelian randomization (MR) method was employed to explore the genetic associations between DHDB and SDL. The DHDB variables studied encompassed Alcohol Intake (ALI), Alcohol Intake Frequency (ALF), High-Frequency Drinking with Meals (HAL), Tea Intake (TEAI), Coffee Intake (COFI), and Red Wine Intake (RWI). The SDL variables analyzed were Insomnia (INS), Inhibit Excitability (IE), and Sleep Duration (SD).ResultsThe MR analysis identified genetic links between ALI and INS, ALF and IE, ALF and SD, HAL and INS, HAL and IE, HAL and SD, TEAI and IE, TEAI and SD, and COFI and IE (P(IVW)&lt;0.05). Nonetheless, no significant genetic links were detected between ALI and IE, ALI and SD, ALF and INS, TEAI and INS, COFI and INS, COFI and SD, RWI and INS, RWI and IE, or RWI and SD (P(IVW)&gt;0.05).ConclusionsAlcohol intake may elevate insomnia risk without affecting daytime sleepiness or sleep duration. Frequent alcohol consumption may lead to daytime sleepiness and reduced sleep duration but not insomnia. Alcohol with meals might reduce insomnia and daytime sleepiness while improving sleep duration. Tea appears unlinked to insomnia and may reduce daytime drowsiness. Coffee may alleviate daytime drowsiness without causing insomnia, and red wine shows no significant association with sleep disorders. Reverse MR suggests potential links between sleep disorders and alcohol or caffeine intake.

Unveiling the genetic link and pathogenesis between psoriasis and IgA nephropathy based on Mendelian randomization and transcriptome data analyses.

It has been reported that many people with psoriasis have been diagnosed with secondary IgA nephropathy (IgAN). However, the mechanisms behind the association between psoriasis and IgAN have not been well clarified. The connection between psoriasis and IgAN deserves deeper exploration. Mendelian randomization (MR) analysis would be employed to explore the link of causality between IgAN and psoriasis, psoriasis vulgaris, other and unspecified psoriasis, guttate psoriasis, and arthropathic psoriasis. Transcriptomic analyses were carried out against the Gene Expression Omnibus databases. We identified crosstalk genes through the analysis of Differentially expressed genes and weight gene co-expression network analysis. Functional annotations were enriched for these crosstalk genes. Subsequently, we established a protein-protein interaction network, and candidate genes would be discovered through the utilization of the MCODE and CytoHubba plug-in applications. Lastly, the predictive efficacy of these genes was examined via creating receiver operating characteristic curves. The MR analysis suggested that psoriasis vulgaris patients were at a higher risk for IgAN. [OR = 1.040, 95%CI (1.005,1.076), p = 0.026 < 0.05]. Additionally, arthropathic psoriasis may augment the incidence of IgAN [OR = 1.081, 95%CI (1.040-1.124), p < 0.01] in the European population. Through the analysis of DEGs and WGCNA, we identified 12 significant genes (NETO2, RRM2, SLAMF7, GBP1, KIF20A, CCL4, MMP1, IL1β, NDC80, CXCL9, C15orf48, GSTA3), which may be potential crosstalk genes between the two diseases. Then, the functional annotation results indicated that the crosstalk genes seemed primarily involved in immune and inflammatory responses. By establishing the PPI network, we further discovered that CXCL9, IL1β, CCL4, and MMP1 play a vital part in psoriasis and IgAN, and all have good diagnostic values. Our MR analysis provided evidence that genetic vulnerability to IgAN may be associated with an elevated risk of psoriasis vulgaris and arthropathic psoriasis respectively among Europeans. Doctors should be aware of these associations when patients with psoriasis present with renal dysfunction, especially those with psoriasis vulgaris and arthropathic psoriasis. Chronic inflammation, drug effects, and immunity may contribute to the generation and development of both diseases. IL1β, CXCL9, CCL4, and MMP1 may be core biomarkers for psoriasis and IgAN.

A Unique Case of Adoption in Golden Snub-Nosed Monkeys

Adoption among nonhuman primates (hereafter primates) has been widely reported, particularly in chimpanzees, renowned for their higher intelligence and well-developed cognition. In contrast to adoption in other Old World monkeys, this case of adoption in golden snub-nosed monkeys (Rhinopithecus roxellana) involves two infants associated with three units characterized by distinct social structures and reproductive functions. Consequently, this case extends beyond traditional hypotheses on allomaternal care and adoption—such as enhancing the fitness of adoptive mothers, fostering maternal behaviors, and improving fitness through social and individual interactions—to necessitate an association with the complex social structure characterized by hierarchical, multilevel composition, akin to human society, and intense sexual selection that frequently results in infanticide. Specifically, adopting an infant with a genetic link to the dominant male of the adopting female may reduce the risk of infanticide against her offspring that do not share a biological link with the dominant male. This adoption pattern suggests that golden snub-nosed monkeys may possess more sophisticated intelligence and cognition, characteristics supported by more developed brain structure and facial muscles than the other Old World monkeys.

Genomic structural equation modeling reveals latent phenotypes in the human cortex with distinct genetic architecture

Genetic contributions to human cortical structure manifest pervasive pleiotropy. This pleiotropy may be harnessed to identify unique genetically-informed parcellations of the cortex that are neurobiologically distinct from functional, cytoarchitectural, or other cortical parcellation schemes. We investigated genetic pleiotropy by applying genomic structural equation modeling (SEM) to map the genetic architecture of cortical surface area (SA) and cortical thickness (CT) for 34 brain regions recently reported in the ENIGMA cortical GWAS. Genomic SEM uses the empirical genetic covariance estimated from GWAS summary statistics with LD score regression (LDSC) to discover factors underlying genetic covariance, which we are denoting genetically informed brain networks (GIBNs). Genomic SEM can fit a multivariate GWAS from summary statistics for each of the GIBNs, which can subsequently be used for LD score regression (LDSC). We found the best-fitting model of cortical SA identified 6 GIBNs and CT identified 4 GIBNs, although sensitivity analyses indicated that other structures were plausible. The multivariate GWASs of the GIBNs identified 74 genome-wide significant (GWS) loci (p < 5 × 10−8), including many previously implicated in neuroimaging phenotypes, behavioral traits, and psychiatric conditions. LDSC of GIBN GWASs found that SA-derived GIBNs had a positive genetic correlation with bipolar disorder (BPD), and cannabis use disorder, indicating genetic predisposition to a larger SA in the specific GIBN is associated with greater genetic risk of these disorders. A negative genetic correlation was observed between attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD). CT GIBNs displayed a negative genetic correlation with alcohol dependence. Even though we observed model instability in our application of genomic SEM to high-dimensional data, jointly modeling the genetic architecture of complex traits and investigating multivariate genetic links across neuroimaging phenotypes offers new insights into the genetics of cortical structure and relationships to psychopathology.

Unraveling shared and unique genetic causal relationship between gut microbiota and four types of uterine-related diseases: Bidirectional Mendelian inheritance approaches to dissect the "Gut-Uterus Axis"

BackgroundThe gut microbiota has emerged as a pivotal factor in the etiology of uterine-related diseases. This study aims to elucidate the genetic causal link between gut microbiota composition and these conditions, focusing on the systemic impact and uterine pathology to better understand the "Gut-Uterus Axis." MethodsWe utilized pooled data from two different GWAS databases, including data from 209 gut microbiota traits and data from four uterus-related diseases. Bidirectional Mendelian Randomization (MR) approaches, incorporating Bayesian weighting and traditional inverse variance weighting (IVW) methods, were employed to explore causal relationships. The robustness of findings was ensured through sensitivity analyses, outlier testing, and MR-PRESSO analysis. ResultsSeventeen significant associations were identified between gut microbiota traits and uterine-related diseases, suggesting potential causal links. These associations were consistent across sensitivity analyses, affirming the reliability of our results. Conversely, reverse MR analyses did not reveal statistically significant associations between uterine diseases and bacterial traits, indicating a unidirectional influence of gut microbiota on uterine health. These findings highlight the complex interplay within the "Gut-Uterus Axis." ConclusionThis research establishes a causal relationship between gut microbiota and uterine diseases, advocating for targeted interventions to mitigate associated risks. It underscores the interconnectedness of gut and reproductive health, promoting a holistic approach to management and treatment within the "Gut-Uterus Axis".

Geochemistry and Zircon U–Pb Chronology of Jinchanshan Gold-Hosted Granitoids, Inner Mongolia: Implications for Petrogenesis and Geodynamic Evolution

Jinchanshan is a medium-sized, granitoid-hosted gold deposit located in the Kalaqin area of Inner Mongolia. Mineralization predominantly occurs in the contact zone between biotite granites and quartz porphyry rocks, associated with the Jinchanshan minor intrusion, suggesting a genetic link to the granitoid-hosted gold deposit. In this study, the petrography, geochemistry, and LA-ICP-MS zircon U–Pb chronology of these two granitoid samples were studied. The results indicate that the zircon U–Pb age of the biotite granites is 127.9 ± 3.0 Ma, while that of the quartz porphyry is 121.4 ± 1.5 Ma, both dating back to the Early Cretaceous. The average SiO2 content of the granites is 66.64%, and the rocks have high total alkali (K2O + Na2O) content, averaging 9.13%. The average K2O content is 4.39%, with a K2O/Na2O ratio of 0.93. The quartz porphyry rocks are enriched in SiO2 (74.41%–76.85%) and have high Na2O + K2O content (8.67%–9.59%), but are low in MgO (0.03%–0.09%), CaO (0.44%–1.02 %), and TiO2 (0.08%–0.12%). Most samples of the biotite granite and the quartz porphyry rocks exhibit high-K peraluminous and medium-K calc-alkaline characteristics, respectively. Both rock types are enriched in Rb, Th, U, K, Zr, Hf, and Gd and relatively depleted in Ba, Sr, P, Ti, Nb, Ta, and Eu, with a pronounced negative Eu anomaly. The biotite granites show high ∑LREE/∑HREE ratios (6.1–6.9), while the quartz porphyry rocks exhibit lower ratios (2.0–4.2). Both granitoid types have elevated FeOT content and FeOT/(FeOT + MgO) ratios, indicating that the Jinchanshan granitoids are A-type granites. The zircon U–Pb ages, combined with the regional tectonic settings, suggest that these granitoids formed during large-scale metallogenic events in the Early Cretaceous, within the Yanshanian post-orogenic extensional tectonic regime. This is consistent with the lithospheric thinning and extensional processes in Eastern China during this period.

Genetic relationship between W mineralization and granitic intrusion in Nanling Region, South China: Constraints from zircon and cassiterite u-pb age from new drill holes in Shangping deposit

The Nanling metallogenic belt is known for the widely development of typical quartz vein type W deposit. These quartz veins that contain wolframite are frequently located in close proximity to granitic intrusions. The genetic relationship between tungsten mineralization and the associated granitic rocks is still a subject of controversy. The Shangping deposit stands out as a historically significant W deposit with a quartz vein type in the region of Nanling. However, the specific time that W mineralization occurred remains enigmatic. Granitic intrusions are absent from the mine and only granite porphyry dike is exposed, so the link between tungsten mineralization and magmatic activity remains unclear. Fortunately, in recent years, a concealed granite intrusive has been exposed in drill holes in the southeastern of the Shangping W deposit. To comprehensively address the connection between granitic magma activity and W mineralization, it is vital to make up a relative deficiency of geochronological information on granite and ore mineral. Here, in order to get the first direct age constraints on the origin of the Shangping W deposit, we use a combination of different techniques, incorporating the Hf isotope geochemistry of zirconium and cassiterite U-Pb assessment using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Based on these robust data, we tentatively evaluated the connection between W mineralization and granitic intrusion.For the granite porphyry, the majority of representative U-Pb zircon assays establish a206Pb/238U age of 150.2 ± 0.5 Ma. An inferred emplacement age of ca. 151 Ma for the concealed granite in Kengweiwo is supported by a U-Pb isochron age from zircon. Combined with Hf isotopic characterization, it illuminates the mineralization potential of the Kengweiwo concealed granite. Cassiterite grains from hydrothermal quartz vein are subhedral to anhedral and have a lower intercept 206Pb/238U age of 153.9 ± 1.0 Ma. For the Shangping W deposit, all of these new geochronological dates provide well-constrained mineralization ages of 150–154 Ma. The dates of the concealed granite in the Kengweiwo area and the tungsten mineralization in the Shangping area are extremely concordant, indicating that they occurred roughly concurrently. The vein type tungsten mineralization in Shangping deposit may has a genetic link with crystallization of uncovered granite present at depth, which requires further investigation. These results emphasize the significance and potential of concealed granitic intrusion to host disseminated W mineralization in the deep part of Shangping deposit.

Hydrothermal rutile chemistry and U-Pb age fingerprinting of the formation of the giant Nurkazgan porphyry Cu-Au deposit, Central Kazakhstan

The porphyry Cu-related intrusions commonly comprise multiple phases such as the large Nurkazgan porphyry Cu-Au deposit in Central Kazakhstan, hosted in the Karagandinsky dioritic to granitic intrusive complex. Here, SHRIMP and LA-ICP-MS zircon U-Pb dating on the multiple ore-bearing intrusions from this complex confirms a punctuated magmatic history distributed over 35 m.y., and marked by three episodic porphyry events rather than a single event, with the oldest event being the early granodiorite and quartz diorite porphyries at ca. 437–440 Ma, the second being the quartz diorite porphyry at 429.7 ± 2.1 Ma, and the last being the late granodiorite and quartz diorite porphyries at 402.8 ± 3.7 Ma and 402.0 ± 3.9 Ma, respectively. The mineralization is related to the two younger episodic intrusions of quartz diorite porphyry at ∼ 430 Ma and ∼ 402 Ma, respectively. SIMS U-Pb dating of hydrothermal, Cu-rich (up to 20.9 ppm) rutile from the breccia-type ores directly constrains the timing of porphyry mineralization at 428.9 ± 6.9 Ma, which is coincident with the emplacement age of the ∼ 430 Ma quartz diorite porphyry, and thus demonstrates this porphyry as a causative intrusion generating main-stage mineralization. This close genetic link is also supported by the chondrite-normalized REE patterns of rutile, which show remarkably similar light REE-enrichments and moderate negative Eu anomalies to those of the ∼ 430 Ma quartz diorite porphyry. A molybdenite sample obtained from the main-ore stage vein, however, has a Re-Os age of 418.6 ± 1.8 Ma, which is slightly younger than the U-Pb age determinations of rutile. This indicates that the Re-Os isotope system was disturbed by the second (post-ore) thermal event related to ∼ 402 Ma quartz diorite porphyry. In line with published data, this study suggests that the rutile U-Pb age in combination with its REE patterns can be a powerful tool to trace the causative porphyry. Moreover, the typical LREE-enriched REE patterns coupled with the high Cu anomalies, inherited from the causative porphyry and related exsolving fluids, can be as diagnostic proxies for distinguishing the porphyry Cu-related hydrothermal rutile from those formed in orogenic gold deposits. Based on these two geochemical discriminators and U-Pb ages, rutile can serve as unique fingerprints to help improve porphyry copper exploration in green field or covered terranes to complement detrital zircon fertility indicators.

Investigating the genetic causal relationship between breast cancer and endometrial cancer: A two-sample Mendelian randomization study.

Observational studies have consistently shown a correlation between breast cancer (BC) and endometrial cancer (EC). Despite these findings, the causal relationship between these cancers has not been clearly defined. This research employed a bidirectional two-sample Mendelian randomization to explore the genetic causality between BC and EC. Genetic instruments for BC were derived from the Breast Cancer Association Consortium genome-wide association studies summary statistics, while for EC, data were sourced from the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium, and the UK Biobank. The primary analytical method was inverse-variance weighted. Additional analyses, such as MR-Egger and weighted median, were conducted to validate the robustness of our findings from multiple perspectives. The MR-Egger intercept test was conducted to examine potential pleiotropy, whereas Cochrane Q test was implemented to assess heterogeneity. A leave-one-out analysis was conducted to assess the sensitivity of the observed association. Our analysis identified a bidirectional genetic causal relationship between estrogen receptor-positive breast cancer (ER+BC) and EC. Inverse-variance weighted analysis indicated an odds ratio of 1.0686 (95% confidence interval: 1.0029-1.1386, P = .0403) from ER+BC to EC and an odds ratio of 1.0692 (95% confidence interval: 1.0183-1.1225, P = .0071) from EC to ER+BC. No significant horizontal pleiotropy was detected. This study confirms a bidirectional genetic link between ER+BC and EC, suggesting shared genetic etiologies and possibly linked pathophysiological pathways. Understanding the genetic interplay between ER+BC and EC can enhance strategies for the precise prevention and screening of these prevalent cancers, potentially leading to improved clinical outcomes and management of secondary primary malignancies.

Role of blood metabolites in mediating the effect of gut microbiota on chronic gastritis.

Exploring the link between gut microbiota and chronic gastritis (CG), and assessing the potential mediating influence of blood metabolites. Using aggregated data from genome-wide association studies (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to explore the genetic links between gut microbiota (412 types) and CG (623,822 cases). Furthermore, we utilized a two-step MR approach to measure the extent to which blood metabolites (1,400 types) mediate the impact of gut microbiota on CG. Through MR, we identified that three genetically predicted gut microbiota increased the risk of CG: the ubiquinol-8 biosynthesis pathway (OR 1.149, 95%CI 1.022-1.291), Odoribacter from the Porphyromonadaceae family (OR 1.260, 95%CI 1.044-1.523), and Coprococcus from the Lachnospiraceae family (OR 1.125, 95%CI 1.010-1.253). Currently, there is no evidence to suggest that genetically predicted CG affects the risk of gut microbiota. Four blood metabolites mediated the proportionate changes in genetically predicted gut microbiota: levels of 4-hydroxyphenylacetate levels by 14.9% (95% CI -0.559%, 30.3%), palmitoleate (16:1n7) levels, and the phosphate to alanine ratio together mediated the same microbiota by 6.97% (95% CI -1.61%, 15.6%) and 7.91% (95% CI -1.67%, 17.5%), while the phosphate to alanine ratio and X-12839 levels together mediated the same microbiota by 8.48% (95% CI -2.87%, 19.8%) and 10.7% (95% CI 0.353%, 21.1%). In conclusion, our research has confirmed a causal link between gut microbiota, blood metabolites, and CG. Metabolites such as 4-hydroxyphenylacetate levels, palmitoleate (16:1n7) levels, the phosphate to alanine ratio, and X-12839 levels have relatively significant mediating roles between gut microbiota and CG. These metabolites may influence the occurrence and development of CG by regulating inflammatory responses, energy metabolism, and gut barrier function. However, the majority of the influence of gut microbiota on CG remains unclear, necessitating further research into other potential mediating risk factors. Clinically, it is crucial to focus on patients suffering from CG who exhibit dysbiosis of gut microbiota.IMPORTANCEThe results indicate that interactions between particular gut microbiota and blood metabolites may significantly contribute to the onset and progression of CG. These findings offer new insights and potential targets for early diagnosis, personalized treatment, and prevention of CG.

Cassiterite and zircon U-Pb ages and compositions from ore-bearing and barren granites in Thailand: Constraints on the formation of tin deposits in Southeast Asia

The Southeast Asian Tin Province comprises western, central, and eastern belts and hosts significant granite-related Sn deposits. The genetic links between granites and Sn mineralization are still unclear. Most Sn deposits are in Thailand’s western and central belts, but their origin remains poorly elucidated due to the absence of direct dating of mineralization. Herein in-situ U-Pb age data of wolframite and cassiterite grains from nine representative Sn deposits in Thailand are obtained, which fall into two stages. Triassic deposits (224–210 Ma) are found in the Central belt, with Cretaceous deposits (78–67 Ma) in the Central belt being younger than those in the Western belt (84–74 Ma). However, ore-bearing granites, spanning two periods (227–205 Ma and 85–69 Ma), occur in central and western belts. Some Triassic ore-bearing granites exhibit significantly older ages than ore-forming ages. Newly identified ore-forming granites contain zircon grains with relatively low εHf(t) values (−29.5 to + 4.1; average = − 11.8), indicative of an origin from supracrustal sediments from the Sibumasu block. In contrast, barren granites have ages from 303–224 Ma and higher zircon εHf(t) values (−9.9 to + 13.2; average = +1.2), which suggests that they were derived from the juvenile mafic crust. Even after experiencing hydrothermal fluids exsolution, some low-fractionated ore-forming granites (D.I. < 90) still maintain remarkably high tin contents. Both ore-forming and barren granites crystallized under reducing conditions. Our study highlights the importance of Sn-rich sources of parental magmas in forming Sn deposits. The metasediment-rich basement of the Sibumasu block distributing along the continental margin is likely the Sn-rich source. These sources played a crucial role in forming two stages of tin deposits in distinct tectonic settings, that are syn-collisional crustal thickening in Paleo-Tethys and post-collisional extension-related settings in Neo-Tethys.

Anorexia nervosa with comorbid autism spectrum disorder: Optimizing care for youth, caregivers, and health care providers

Abstract Youth with anorexia nervosa (AN) have been reported to have high levels of comorbid autism spectrum disorder (ASD) and ASD-like traits suggesting a potential shared underlying neurodevelopmental or genetic link between the disorders. Youth with comorbid AN and ASD symptomatology generally require more intensive treatment and have worse psychological outcomes following treatment. To date, no Canadian national guidelines exist for the treatment of this comorbidity. An informal survey of tertiary paediatric eating disorder programs across Canada revealed that centres do not routinely screen for ASD at intake and few offer any treatment modifications for youth with AN and suspected/diagnosed comorbid ASD. This represents a significant care gap for this clinical sub-population and an important area for future study and healthcare provider training.