Genetic Causation Research Articles

Epilepsy and psychiatric comorbidities: A bidirectional mendelian randomization study

Study objectivesPsychiatric comorbidities are relatively common among patients with epilepsy; however, the underlying mechanisms of this association remain largely unknown. The objective of this Mendelian randomization (MR) study was to analyze the genetic correlations and causality underlying these reciprocal associations. MethodsSingle-nucleotide polymorphisms associated with epilepsy (29,677 controls and 15,212 cases) and seven psychiatric comorbidities (485,436 controls and 269,495 cases) were identified from genome-wide association studies. Causal significance was estimated using inverse variance weighting. Sensitivity analyses included the weighted median, MR-Egger, and MR-PRESSO. The psychiatric comorbidities analyzed in this study included attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder (OCD), and anorexia nervosa. ResultsBoth forward and reverse genetic associations were observed for the selected psychiatric disorders. Notably, ADHD was significantly associated with an increased risk of generalized epilepsy (odds ratio [OR], 1.09; 95 % confidence interval [CI], 1.01–1.18; p = 0.013). However, MR-PRESSO detected the existence of pleiotropy (p = 0.001). Additionally, focal epilepsy was significantly associated with a higher risk of OCD (OR, 1.44; 95 % CI, 1.08–1.92; p = 0.013), and all sensitivity tests yielded favorably nonsignificant results. There was no significant genetic association between epilepsy and other examined psychiatric disorders. However, due to the detection of pleiotropy by MR-Egger and considerations related to the threshold for genetic instruments, a cautious approach is warranted in interpreting some of the results. ConclusionsThis study revealed significant genetic causality between focal epilepsy and OCD, as well as between ADHD and generalized epilepsy. However, no casual significance was observed with other psychiatric comorbidities examined. Considering the inherent limitations of MR studies, further research is warranted to definitively clarify these genetic causal associations.

Late age at first birth is a protective factor for oesophageal cancer and gastro-oesophageal reflux: the evidence from the genetic study.

The primary objective of this research endeavor was to examine the underlying genetic causality between the age at first birth (AFB) and four prevalent esophageal diseases, namely oesophageal obstruction (OO), oesophageal varices (OV), gastro-oesophageal reflux (GOR), and oesophageal cancer (OC). We conducted a two-sample Mendelian randomization (MR) analysis to examine the causal association between AFB and four prevalent esophageal disorders. We employed eight distinct MR analysis techniques to evaluate causal relationships, encompassing random-effects inverse variance weighted (IVW), MR Egger, weighted median, simple mode, weighted mode, maximum likelihood, penalized weighted median, and fixed-effects IVW. The random-effects IVW method served as the primary approach for our analysis. Furthermore, we executed several sensitivity analyses to assess the robustness of the genetic causal inferences. The random-effects IVW analysis revealed a significant negative genetic causal association between AFB and both GOR (P < 0.001, Odds Ratio [OR] 95% Confidence Interval [CI] = 0.882 [0.828-0.940]) and OC (P < 0.001, OR 95% CI = 0.998 [0.998-0.999]). Conversely, there was insufficient evidence support to substantiate a genetic causal link between AFB and OO (P = 0.399, OR 95% CI = 0.873 [0.637-1.197]) or OV (P = 0.881, OR 95% CI = 0.978 [0.727-1.314]). The results of sensitivity analyses underscore the robustness and reliability of our MR analysis. The findings of this investigation substantiate the notion that elevated AFB confers a protective effect against GOR and OC. In addition, no causative association was discerned between AFB and OO or OV at the genetic level.

Genetic causal association between frozen shoulder and carpal tunnel syndrome: a two-sample mendelian randomization

ObjectiveObservational studies have suggested an association between frozen shoulder (FS) and carpal tunnel syndrome (CTS). However, due to challenges in establishing a temporal sequence, the causal relationship between these two conditions remains elusive. This study, based on aggregated data from large-scale population-wide genome-wide association studies (GWAS), investigates the genetic causality between FS and CTS.MethodsInitially, a series of quality control measures were employed to select single nucleotide polymorphisms (SNPs) closely associated with the exposure factors. Two-sample Mendelian randomization (MR) was utilized to examine the genetic causality between FS and CTS, employing methods including Inverse-Variance Weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and Weighted Mode approaches. Subsequently, sensitivity analyses were conducted to assess the robustness of the MR analysis results.ResultsIVW analysis results indicate a positive causal relationship between CTS and FS (p < 0.05, OR > 1), while a negative causal relationship between the two conditions was not observed. Heterogeneity tests suggest minimal heterogeneity in our IVW analysis results (p > 0.05). Multivariable MR testing also indicates no pleiotropy in our IVW analysis (p > 0.05), and stepwise exclusion tests demonstrate the reliability and stability of the MR analysis results. Gene Ontology (GO) pathway analysis reveals enrichment of genes regulated by the associated SNPs in the TGFβ-related pathways.ConclusionThis study provides evidence of the genetic causal association between frozen shoulder and carpal tunnel syndrome and provides new insights into the genetics of fibrotic disorders.

Genetic causality and site-specific relationship between sarcopenia and osteoarthritis: a bidirectional Mendelian randomization study.

Background: Previous studies demonstrated a controversial relationship between sarcopenia (SP) and osteoarthritis (OA) and their genetic causality is unclear. Thus, we conducted a Mendelian randomization (MR) analysis to evaluate the possible causal association between sarcopenia-related traits (appendicular lean mass (ALM), grip strength, usual walking pace) and OA. Method: We used pooled genetic data from the UK Biobank for ALM(n = 450,243), left-hand grip strength (n = 461,026), right-hand grip strength (n = 461,089) and usual walking pace (n = 459,915). Moreover, summary statistics for OA were obtained from the latest study conducted by the Genetics of Osteoarthritis Consortium, including all OA (n = 826,690), hand OA (n = 303,7782), hip OA (n = 353,388) and knee OA (n = 396,054). The primary method for estimating causal effects was the inverse-variance weighted (IVW) method, with the utilizing of false discovery rate adjusted p values (P FDR). Additional MR methods such as MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), weighted median were employed as supplementary analyses. Results: We discovered ALM (odds ratio (OR) = 1.103, 95% confidence interval (CI) = 1.052-1.156, P FDR = 2.87E-04), hand grip strength (left, IVW OR = 0.823, 95% CI = 0.712 to 0.952, P FDR = 0.020; right, OR = 0.826, 95% CI = 0.718 to 0.950, P FDR = 0.020), and usual walking pace (OR = 0.339, 95% CI = 0.204 to 0.564, P FDR = 2.38E-04) were causally associated with OA risk. In the reverse MR analysis, we identified a causal effect of OA on ALM (β = -0.258, 95% CI = -0.369 to 0.146, P FDR = 0.6.07E-06), grip strength (left, β = -0.064, 95% CI = -0.104 to 0.024, P FDR = 0.002; right, β = -0.055, 95% CI = -0.095 to 0.014, P FDR = 0.008), and usual walking pace (β = -0.104, 95% CI = -0.147 to 0.061, P FDR = 1.61E-05). Conclusion: This present study suggests an obvious causality of SP on OA, with condition exhibiting site-specific effects, while evidence was also provided for the causal effect of OA on SP.

No genetic link between Parkinson's disease and SARS-CoV-2 infection: a two-sample Mendelian randomization study.

Existing literature has not clearly elucidated whether SARS-CoV-2 infection increases the incidence of Parkinson's disease or if Parkinson's disease patients are more susceptible to the effects of SARS-CoV-2 infection. To clarify the issue, this study employs a genetic epidemiological approach to investigate the association. This study utilizes a two-sample Mendelian randomization analysis. The primary analysis employs the inverse variance-weighted (IVW) method, supplemented by secondary analyses including MR-Egger regression, weighted median, IVW radial method, and weighted mode, to evaluate the bidirectional causal relationship between Parkinson's disease and SARS-CoV-2 infection. IVW results showed no genetic causality between SARS-CoV-2 susceptibility, hospitalization rate and severity and Parkinson's disease. (IVW method: p = 0.408 OR = 1.10 95% CI: 0.87 ~ 1.39; p = 0.744 OR = 1.11 95% CI: 0.94 ~ 1.09; p = 0.436 OR = 1.05 95% CI: 0.93 ~ 1.17). Parkinson's disease was not genetically associated with susceptibility to new crown infections, hospitalization rates, and severity (IVW method: p = 0.173 OR = 1.01 95% CI: 0.99 ~ 1.03; p = 0.109 OR = 1.05 95% CI: 0.99 ~ 1.12; p = 0.209 OR = 1.03 95% CI: 0.99 ~ 1.07). MR-Egger regression, weighted median, IVW radial method, and weighted mode results are consistent with the results of the IVW method. This study does not support a genetic link between Parkinson's disease and SARS-CoV-2 infection, and the association observed in previous cohort studies and observational studies may be due to other confounding factors.

Please Provide the Following Information: Enthymemes and the Logics of Individual Responsibility in the Patient Medical History Form

ABSTRACT Despite the overwhelming evidence that health and risk are multifactorial, medical texts that interface with publics continue to circulate logics of individual responsibility of health. This article analyzes patient medical history forms across different times and spaces to track the logics of individual responsibility that operate in the form in various contexts. The analysis finds logics of individual responsibility are enthymized through genetic causation and personal choice and makes the case that texts, including mundane forms, perform patient education and construct patients’ identifications with health, illness, and risk.

Exploration of the causal effects of leukocyte telomere length and four gastrointestinal diseases: a two-sample bidirectional Mendelian randomization study

BackgroundTo explore the underlying causality between leukocyte telomere length (LTL) and four gastrointestinal diseases, we designed a two-sample bidirectional Mendelian randomization study.MethodsTwo-sample Mendelian randomization (MR) was used to explore genetic causality between LTL and four gastrointestinal diseases, including irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), gastrointestinal ulcers disease (GUD), and nonalcoholic fatty liver disease (NAFLD). We utilized inverse-variance weighted (IVW) as the primary method for MR analysis. Supplementary analyses were conducted using methods such as MR-Egger regression, weighted-median, Maximum Likelihood (MaxLik), Robust adjusted profile score (MR-RAPS), Contamination mixture (ConMix), and MR-mix. Cochran’s Q was calculated to check for heterogeneity. The MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) were detected for pleiotropy.ResultsThe IVW analysis suggests that there may be a potential causal relationship between LTL and two diseases (odds ratio (OR): 1.062; 95% confidence interval (CI): 1.003, 1.124; p = 0.038 for IBS and OR: 0.889; 95% CI: 0.798, 0.990; p = 0.032 for GERD). However, other methods do not entirely align with the results of the IVW analysis. In the reverse MR analysis, we did not find statistically significant associations between LTL and these four diseases.ConclusionThe current evidence does not definitively rule out a causal relationship between LTL and these four gastrointestinal diseases but suggests a potential association between LTL and IBS, or LTL and GERD. Exploring the relationship between gastrointestinal diseases and LTL may offer new insights into the onset, progression, and treatment of these diseases.

No evidence of genetic causality between diabetes and osteonecrosis: a bidirectional two-sample Mendelian randomization analysis

ObjectiveThis study aimed to examine whether diabetes mellitus is causally associated with osteonecrosis.MethodUsing publicly accessible genome-wide association study statistics, a bidirectional two-sample Mendelian randomization analysis was carried out. In order to determine whether diabetes has a causal effect on osteonecrosis and whether osteonecrosis has a causal effect on diabetes, we extracted six date on diabetes in Europeans from IEU OpenGWAS and GWAS Catalogue and osteonecrosis in Europeans from FinnGen. We then evaluated the data using inverse variance weighting, MR-Egger regression, weighted median, weighted mode, and simple mode. The results’ stability and dependability were then evaluated using sensitivity analysis and heterogeneity analysis. Finally, meta-analysis is used to further confirm if there is a relationship between diabetes and osteonecrosis.ResultsWhen diabetes was used as an exposure factor, MR-Egger regression showed that directional fold product was unlikely to bias the results. Cochran’s Q test showed only minor heterogeneity in a few data sets. Multidirectional tests Egger-intercept, MR-PRESSO and funnel plots for most data did not show multidirectional and asymmetry at the gene level. Most of the IVW results showed no causal relationship between diabetes mellitus and osteonecrosis. The results of meta-analysis of IVW methods further confirmed the absence of a causal relationship. Inverse MR analysis also showed no causal relationship between osteonecrosis and diabetes.ConclusionResults of bidirectional MR analysis show no evidence of causal relationship between diabetes and osteonecrosis.

Lipid Metabolism, Methylation Aberrant, and Osteoporosis: A Multi-omics Study Based on Mendelian Randomization.

Observational studies have shown a causal association between dyslipidemia and osteoporosis, but the genetic causation and complete mechanism of which are uncertain. The disadvantage of previous observational studies is that they are susceptible to confounding factors and bias, that makes it difficult to infer a causal link between those two diseases. Abnormal epigenetic modifications, represented by DNA methylation, are important causes of many diseases. However, there are no studies showing a bridging role for methylation modifications in blood lipid metabolism and osteoporosis. SNPs for lipid profile (Blood VLDL cholesterol (VLDL-C), blood LDL cholesterol (LDL-C), blood HDL cholesterol (HDL-C), blood triglycerides (TG), diagnosed pure hypercholesterolaemia, blood apolipoprotein B (Apo B), blood apolipoprotein A1(Apo A1)), and bone mineral density (BMD) in different body parts (Heel BMD, lumbar BMD, whole-body BMD, femoral neck BMD) were obtained from large meta-analyses of genome-wide association studies as instrumental variables for two-sample Mendelian randomization. Assessment of the genetic effects of lipid profile-associated methylation sites and bone mineral density was carried out using the summary-data-based Mendelian randomization (SMR) method. Two-sample Mendelian randomization showed that there was a negative causal association between hypercholesterolaemia and heel BMD (p = 0.0103, OR = 0.4590), and total body BMD (p = 0.0002, OR = 0.2826). LDL-C had a negative causal association with heel BMD (p = 8.68E-05, OR = 0.9586). VLDL-C had a negative causal association with heel BMD (p = 0.035, OR = 0.9484), lumbar BMD (p = 0.0316, OR = 0.9356), and total body BMD (p = 0.0035, OR = 0.9484). HDL-C had a negative causal association with heel BMD (p = 1.25E-05, OR = 0.9548), lumbar BMD (p = 0.0129, OR = 0.9358), and total body BMD (p = 0.0399, OR = 0.9644). Apo B had a negative causal association with heel BMD (p = 0.0001, OR = 0.9647). Apo A1 had a negative causal association with heel BMD (p = 0.0132, OR = 0.9746) and lumbar BMD (p = 0.0058, OR = 0.9261). The p-values of all positive results corrected by the FDR method remained significant and sensitivity analysis showed that there was no horizontal pleiotropy in the results despite the heterogeneity in some results. SMR identified 3 methylation sites associated with lipid profiles in the presence of genetic effects on BMD: cg15707428(GREB1), cg16000331(SREBF2), cg14364472(NOTCH1). Our study provides insights into the potential causal links and co-pathogenesis between dyslipidemia and osteoporosis. The genetic effects of dyslipidaemia on osteoporosis may be related to certain aberrant methylation genetic modifications.

The undue influence of genetic information on senior medical students’ treatment decisions

BackgroundKnowledge of the genetic basis of health conditions can influence how the public perceives their own and others’ health. When there are known genetic associations for such conditions, genetic essentialist biases facilitate deterministic thinking and an over-emphasis of genetic causality. This study investigates the role that genetic essentialist biases play in medical decision-making.MethodsSenior postgraduate medical students (N = 102) read a scenario in which a patient presents with gastroenterological symptoms. Half of the students were told that the patient tested positive for HLADQ2 – a gene implicated in, but not deterministic of, coeliac disease. The other half received no genetic information. Students were assessed on their recommendations for investigation and management using a multiple-choice questionnaire. Twenty-two of these students participated in a qualitative follow-up which used focus groups and semi-structured interviews to explore the reasoning behind students’ responses.ResultsManagement recommendations differed between the two groups, with those receiving genetic information more likely to recommend a gluten free diet. Recommendations for further investigation did not differ significantly between groups. Interviews suggested that these findings arose despite the students’ good understanding of the common non-deterministic nature of genes, such as HLADQ2.ConclusionDifferences in management recommendations suggest that the inclusion of genetic information unduly biased students towards a premature diagnosis of a serious health condition, coeliac disease. Follow-up interviews introduced the possibility that observed manipulation-based differences may have been based on anticipated expectations of examiners, rather than perceived future clinical practice. Based on the present results it is unclear whether intentional exam-taking strategies fully account for medical students’ decisions, or if they contribute in addition to the activation of genetic essentialist biases. Further research in clinical settings may ascertain whether genetic essentialist biases would truly influence medical student and doctors within their clinical practice environment.

Causal associations between common musculoskeletal disorders and dementia: a Mendelian randomization study.

Dementia and musculoskeletal disorders (MSDs) are major public health problems. We aimed to investigate the genetic causality of common MSDs and dementia. Two-sample Mendelian randomization (MR) was used in this study. MR analysis based on gene-wide association study (GWAS) data on osteoarthritis (OA), dementia with Lewy bodies, and other MSDs and dementia types were obtained from the Genetics of Osteoarthritis consortium, IEU-open GWAS project, GWAS catalog, and FinnGen consortium. Rigorously selected single-nucleotide polymorphisms were regarded as instrumental variables for further MR analysis. Inverse-variance weighted, MR-Egger regression, weight median, simple mode, and weight mode methods were used to obtain the MR estimates. Cochran's Q test, MR-Egger and MR-Pleiotropy Residual Sum and Outlier analysis, and the leave-one-out test were applied for sensitivity testing. The inverse-variance weighted method showed that hip OA was genetically associated with a lower risk of dementia, unspecified dementia, dementia in Alzheimer's disease, and vascular dementia. Kneehip OA was inversely associated with unspecified dementia and vascular dementia. Rheumatoid arthritis, juvenile idiopathic arthritis and seronegative rheumatoid arthritis were inversely associated with frontotemporal dementia, and rheumatoid arthritis was inversely associated with unspecified dementia. Simultaneously, ankylosing spondylitis was an independent risk factor for dementia, dementia with Lewy bodies, and dementia in Alzheimer's disease. Sensitivity tests showed that heterogeneity and horizontal pleiotropy did not exist in these associations. The leave-one-out test showed that these associations were stable. We found that some MSDs were associated with the risk of dementia and provide evidence for the early detection of dementia in patients with MSDs and for the impact of inflammation on the central nervous system.

The Causal Association between Alcohol, Smoking, Coffee Consumption, and the Risk of Arthritis: A Meta-Analysis of Mendelian Randomization Studies

Objective: To evaluate the genetic causality between alcohol intake, smoking, coffee consumption, and arthritis. Methods: Mendelian randomization (MR) studies with alcohol, smoking, and coffee consumption behaviors as exposures, and osteoarthritis (OA) and rheumatoid arthritis (RA) as outcomes were retrieved from up to July 2023. Two researchers with relevant professional backgrounds independently assessed the quality and extracted data from the included studies. Meanwhile, we applied MR analyses of four lifestyle exposures and five arthritis outcomes (two for OA and three for RA) with gene-wide association study (GWAS) data that were different from the included studies, and the results were also included in the meta-analysis. Statistical analyses were performed using Stata 16.0 and R software version 4.3.1. Results: A total of 84 studies were assessed. Of these, 11 were selected for meta-analysis. As a whole, the included studies were considered to be at a low risk of bias and were of high quality. Results of the meta-analysis showed no significant genetic causality between alcohol intake and arthritis (odds ratio (OR): 1.02 (0.94–1.11)). Smoking and arthritis had a positive genetic causal association (OR: 1.44 (1.27–1.64)) with both OA (1.44 (1.22–1.71)) and RA (1.37 (1.26–1.50)). Coffee consumption and arthritis also had a positive genetic causal association (OR: 1.02 (1.01–1.03)). Results from the subgroup analysis showed a positive genetic causality between coffee consumption and both OA (OR: 1.02 (1.00–1.03)) and RA (OR: 1.56 (1.19–2.05)). Conclusion: There is positive genetic causality between smoking and coffee consumption and arthritis (OA and RA), while there is insufficient evidence for genetic causality between alcohol intake and arthritis.

Causal effects of exposure to ambient air pollution on cancer risk: Insights from genetic evidence

Air pollution has been increasingly linked to cancer risk. However, the genetic causality between air pollution and cancer risk remains poorly understood. To elucidate the potential roles of air pollution (NOx, NO2, PM2.5, PM course, and PM10) in the risk of 18 specific-site cancers, large-scale genome-wide association studies with a novel Mendelian randomization (MR) method were employed. Our MR analyses revealed significant associations between certain air pollutants and specific types of cancer. Specifically, a positive association was observed between NOx exposure and squamous cell lung cancer (OR: 1.96, 95%CI: 1.07–3.59, p = 0.03) as well as esophageal cancer (OR: 1.002, 95%CI: 1.001–1.003, p = 0.005). Genetically predicted NO2 exposure was found to be a risk factor for endometrial cancer (OR 1.41, 95%CI: 1.03–1.94, p = 0.03) and ovarian cancer (OR: 1.49, 95%CI: 1.14–1.95, p = 0.0037). Additionally, genetically predicted PM2.5 exposure was associated with an increased risk of ER+ breast cancer (OR: 1.24, 95%CI: 1.03–1.5, p = 0.02) and ER- breast cancer (OR: 2.57, 95%CI: 1.05–6.3, p = 0.04). PM course exposure was identified as a risk factor for glioma (OR: 487.28, 95%CI: 13.08–18,153, p = 0.0008), while PM10 exposure exerted a detrimental effect on mesothelioma (OR: 114.75, 95%CI: 1.14–11,500.11, p = 0.04) and esophageal cancer (OR: 1.01, 95%CI: 1.007–1.02, p = 0.03). These findings underscored the importance of mitigating air pollution to reduce the burden of cancer and highlight the need for further investigations to elucidate the underlying mechanisms involved in these associations.

Rheumatoid arthritis increases the risk of malignant neoplasm of bone and articular cartilage: a two-sample bidirectional mendelian randomization study

ObjectivePrior research has revealed a heightened prevalence of neoplasms in individuals diagnosed with rheumatoid arthritis (RA). The primary objective of this study is to delve into the causal association between RA and two distinct types of neoplasms: benign neoplasm of bone and articular cartilage (BNBAC) and malignant neoplasm of bone and articular cartilage (MNBAC).MethodsWe employed summary data from genome-wide association analyses (GWAS) to investigate the causal relationship between RA and two neoplasms, BNBAC and MNBAC, using a two-sample bidirectional Mendelian randomization (MR) study design. The IEU OpenGWAS database provided the GWAS summary data for RA, while the Finnish consortium supplied the GWAS summary data for BNBAC and MNBAC. Our analysis involved the utilization of eight distinct MR methods, namely random-effects inverse variance weighted (IVW), MR Egger, weighted median, simple mode, weighted mode, maximum likelihood, penalized weighted median, and fixed effects IVW. Subsequently, we conducted assessments to evaluate heterogeneity, horizontal pleiotropy, outliers, the impact of a single-nucleotide polymorphism (SNP), and adherence to the assumption of normal distribution in the MR analysis.ResultsThe results from the MR analysis revealed that there was no significant genetic association between RA and BNBAC (P = 0.427, odds ratio [OR] 95% confidence interval [CI] = 0.971 [0.904–1.044]). However, a positive genetic association was observed between RA and MNBAC (P = 0.001, OR 95% CI = 1.413 [1.144–1.745]). Conducting a reverse MR analysis, we found no evidence to support a genetic causality between BNBAC (P = 0.088, OR 95% CI = 1.041 [0.994–1.091]) or MNBAC (P = 0.168, OR 95% CI = 1.013 [0.995–1.031]) and RA. Our MR analysis demonstrated the absence of heterogeneity, horizontal pleiotropy, and outliers and confirmed that the effect was not driven by a single SNP. Additionally, the data exhibited a normal distribution.ConclusionThe findings of this study demonstrate that RA constitutes a significant risk factor for MNBAC. In the context of clinical application, it is advisable to conduct MNBAC screening in RA patients and remain vigilant regarding its potential manifestation. Importantly, the outcomes of this investigation introduce a fresh vantage point into the understanding of the tumorigenesis associated with RA.

Unraveling genetic causality between type 2 diabetes and pulmonary tuberculosis on the basis of Mendelian randomization

BackgroundThe comorbidity rate between type 2 diabetes mellitus (T2DM) and pulmonary tuberculosis (PTB) is high and imposes enormous strains on healthcare systems. However, whether T2DM is causally associated with PTB is unknown owing to limited evidence from prospective studies. Consequently, the present study aimed to clarify the genetic causality between T2DM and PTB on the basis of Mendelian randomization (MR) analysis.MethodsGenetic variants for T2DM and PTB were obtained from the IEU OpenGWAS project. The inverse variance weighted method was used as the main statistical analysis method and was supplemented with MR-Egger, weighted median, simple mode, and weighted mode methods. Heterogeneity was analyzed using Cochran’s Q statistic. Horizontal pleiotropy was assessed using the MR-PRESSO global test and MR-Egger regression. Robustness of the results was verified using the leave-one-out method.ResultsA total of 152 independent single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to assess the genetic causality between T2DM and PTB. Patients with T2DM had a higher risk of PTB at the genetic level (odds ratio (OR) for MR-Egger was 1.550, OR for weighted median was 1.540, OR for inverse variance weighted was 1.191, OR for simple mode was 1.629, OR for weighted mode was 1.529). There was no horizontal pleiotropy or heterogeneity among IVs. The results were stable when removing the SNPs one by one.ConclusionsThis is the first comprehensive MR analysis that revealed the genetic causality between T2DM and PTB in the East Asian population. The study provides convincing evidence that individuals with T2DM have a higher risk of developing PTB at the genetic level. This offers a significant basis for joint management of concurrent T2DM and PTB in clinical practice.

The causal relationship between sarcopenic obesity factors and benign prostate hyperplasia.

Both benign prostatic hyperplasia (BPH) and sarcopenic obesity (SO) are common conditions among older adult/adults males. The prevalent lifestyle associated with SO is a significant risk factor for the development of BPH. Therefore, we investigated the causal relationship between SO factors and BPH. The instrumental variables for SO factors were selected using the inverse variance-weighted method, which served as the primary approach for Mendelian randomization analysis to assess the causal effect based on summary data derived from genome-wide association studies of BPH. The increase in BMR (OR = 1.248; 95% CI = (1.087, 1.432); P = 0.002) and ALM (OR = 1.126; 95% CI = (1.032, 1.228); P = 0.008) was found to be associated with an elevated risk of BPH. However, no genetic causality between fat-free mass distribution, muscle mass distribution, and BPH was observed. Our findings indicate that a genetic causal association between BMR, ALM and BPH. BMR and ALM are risk factors for BPH. The decrease in BMR and ALM signified the onset and progression of SO, thus SO is a protective factor for BPH.

Deciphering genetic causality between inflammatory bowel disease and periodontitis through bi-directional two-sample Mendelian randomization

Inflammatory bowel disease (IBD) and periodontitis are reported to be closely associated; however, whether there is a causal association between them remains unclear. To explore the existence of this causality, this study applied a bidirectional two-sample Mendelian randomization (MR). The genetic variants were obtained from the summary statistics of genome-wide association studies of IBD, including its subtypes CD and UC, and periodontitis. 175, 148, 113, and six single-nucleotide polymorphisms were selected as instrumental variables for IBD, CD, UC, and periodontitis, respectively. In MR analysis, random-effects inverse-variance weighted was used as the primary method, and weighted median and MR Egger regression were applied as the complementary method. A series of sensitivity analyses were also conducted to ensure the reliability of the results. None of these analyses found a significant effect of genetically proxied IBD and its subtypes on periodontitis, and vice versa. Subsequent sensitivity analyses did not detect any horizontal pleiotropy and heterogeneity. Caution should be exerted when it comes to clinical relevance and further studies are needed to clarify the relationship between IBD and periodontitis.

The association of metabolic syndrome with rotator cuff tendinopathy: a two-sample Mendelian randomization study

BackgroundObservational research reported the underlying correlation of metabolic syndrome (MetS) and its components with rotator cuff tendinopathy (RCT), but their causality remained unclear. This study aimed to investigate whether genetically predicted MetS was related to the risk of RCT.MethodsBoth univariable and multivariable Mendelian randomization (MR) analysis was applied using summary-level data from the most comprehensive genome-wide association studies to estimate the associations of MetS and its component with RCT, with the inverse variance weighted (IVW) as the primary method, and the method of Causal Analysis Using Summary Effect Estimates (CAUSE) as a supplement for false positives detection. The mediation analysis was furtherly used for the assessment of direct and indirect effects.ResultsUnivariable analysis revealed that genetically predicted MetS (OR: 1.0793; 95% CI 1.0311 to 1.1297), body mass index (BMI) (OR 1.2239; 95% CI 1.1357 to 1.3189), and waist circumference (WAC) (OR 1.3177; 95% CI 1.2015 to 1.4451) had a significant positive association with the risk of RCT. Triglycerides and systolic blood pressure were suggestively associated with RCT risk. These associations were also identified by CAUSE. There was independent causality of BMI (OR: 1.1806; 95% CI 1.0788 to 1.2920) and WAC (OR 1.3716; 95% CI 1.2076 to 1.5580) on RCT after adjustment for confounders. No mediator was found in the causal associations.ConclusionOur study revealed the genetic causality of MetS and its components, especially BMI and WAC, with RCT risk. Early prevention and diagnosis of excess central adiposity contributing to MetS are significant in the RCT risk management.

Causal relationship between chronic obstructive pulmonary disease and BMD at different sites: A bidirectional Mendelian randomization study.

Observational studies have demonstrated a correlation between chronic obstructive pulmonary disease (COPD) and osteoporosis (OP). However, it is unclear whether there is genetic causality between COPD and bone mineral density (BMD) reduction at different sites. This study assessed the causal relationship between COPD and BMD in various anatomical locations. Data associated with COPD and BMD were obtained from published genome-wide association studies (GWAS). We selected single nucleotide polymorphisms (SNPs) that were strongly associated with COPD and BMD could serve as instrumental variables for the analysis. Inverse variance weighted, MR-Egger and weighted median were manipulated to evaluate causality. Subsequently, we conducted heterogeneity tests using Cochran Q test and tested for pleiotropy using the MR-Egger intercept. We performed leave-one-out sensitivity analysis to assess the robustness of the results. Additionally, we obtained more accurate causal genetic associations by removing any pleiotropic outlying SNPs and performed Mendelian randomization (MR) analysis with the remaining data. Our findings established that COPD was negatively associated with Heel-BMD (odds ratio[OR] = 0.978, 95% confidence interval [CI] = 0.966, 0.990, P = .0003) but not LS-BMD (OR = 0.981, 95% CI: 0.943, 1.020, P = .335), FA-BMD (OR = 0.984, 95% CI: 0.927, 1.046, P = .616), and FN-BMD (OR = 0.981, 95% CI: 0.950, 1.014, P = .249). In reverse MR analysis, the results showed no significant causal effect of BMD at different sites on COPD. The results were proved to be dependable and steady by sensitivity, heterogeneity, and pleiotropy analysis. We found that COPD increases the risk of decreased heel BMD, however, there is no evidence that the loss of BMD increases the risk of COPD.

Identification of Candidate Genes of Familial Multiple Idiopathic Cervical Root Resorption

IntroductionMultiple idiopathic cervical root resorption (MICRR) is a disease with an unknown etiology that causes invasive cervical root resorption in multiple teeth. Although previous MICRR genomic studies have identified candidate gene variants, the etiology of the condition remains poorly understood. In the present study, we investigated the genetic causality of MICRR to explore candidate variants. MethodsSaliva samples from a family containing 2 affected and two unaffected subjects with the dominant transmission of MICRR were subjected to whole-exome sequencing. ResultsAs a result, we identified novel candidate variants of 10 genes. Each variant was confirmed by Sanger sequencing. Among them, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines classified doublecortin domain containing 1 (c.1099 C > T) and β-defensin 114 (c.189 T > G) as “pathogenic,” and solute carrier family 45 member 2 (c.152_153del) as “likely pathogenic.” ConclusionsThese results provide new insight to help clarify the pathogenesis of MICRR, and the variants could be applied for further investigation to understand invasive cervical root resorption.