A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor

The objective of this study was to investigate whether there is a causal relationship between diabetes mellitus and adhesive capsulitis of shoulder (ACS). A 2-sample Mendelian randomization analysis was performed using publicly available genome-wide association study statistics. To determine whether diabetes was causally associated with ACS, 2 datasets on diabetes among Europeans from the genome-wide association studies catalogue and ACS among Europeans from FinnGen were extracted and the data were analyzed using inverse variance-weighted, Mendelian randomization 123456123451231 Egger regression, weighted medians, weighted modes and simple modes. Sensitivity analysis and heterogeneity analysis were then used to assess the stability and reliability of the results. Mendelian randomization analysis showed causality between type 1 diabetes and ACS (odds ratio = 0.97, 95% confidence interval = 0.85–1.11, P < .05). No significant causal effect of type 2 diabetes on ACS (odds ratio = 0.97, 95% confidence interval = 0.95–1.13, P = .414). The Cochran Q test showed only a low level of heterogeneity between the type 1 diabetes and ACS data sets (Q = 106.0431, P = .045). Not heterogeneous between type 2 diabetes and ACS. Egger-intercept and funnel plots for data did not show multidirectional and asymmetry at the gene level. The study was the first to find a causal association between type 1 diabetes and the risk of developing ACS in European people. No cause-and-effect genetic link was found between type 2 diabetes and shoulder adhesive capsulitis.

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

Background Observational evidence indicates that patients with atrial fibrillation (AF) are at a four- to fivefold increased risk of stroke. By two-sample mendelian randomization (MR), we have shown in our previous work that specifically the cardioembolic stroke subtype is caused by AF. This risk elevation is however variable and appears to be modulated by other risk factors such as hypertension traits and coronary artery disease (CAD). Purpose This study seeks to determine (1) whether genetic predisposition to cardioembolic stroke by AF is independent from modulators, and (2) whether the other stroke subtypes are causally linked with different exposures. Methods The associations between AF, hypertension traits, and CAD as exposures and stroke subtypes as outcomes were individually tested in a two-sample mendelian randomisation (MR) analysis using genetic instruments from publicly available genome-wide association studies (GWAS) in large cohorts. For atrial fibrillation, genetic instruments were obtained from the dataset by Nielsen et al. with 60,620 atrial fibrillation cases and 970,216 controls, collected from six contributing studies including the AFGen Consortium. Associations with stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67, 162 cases; 454, 450 controls). The genetic markers for hypertension traits were taken from a GWAS by Evangelou et al. which combines data from the UK Biobank (UKB) and the International Consortium of Blood Pressure (ICBP) with a total sample size of 757,601 individuals. Genetic instruments for CAD were obtained from the CARDIoGRAMplusC4D consortium (60,801 cases and 123,504 controls from 48 studies). Several MR regression methods such as MR-Egger regression and inverse-variance weighted regression as well as sensitivity analyses were applied. A multivariable MR model served to determine which of the exposures had an independent causal effect on each of the stroke subtypes. Results Atrial fibrillation turned out to be the sole independent causal risk factor for cardioembolic stroke with a beta coefficient of 0.75 (SE = ± 0.04; P = 8.59 x 10e-100) and an OR of 2.16 (1.97-2.27) in a multivariable model adjusted for AF, CAD, systolic blood pressure (SBP) and diastolic blood pressure. In this model, SBP and CAD were non-causative for cardioembolic stroke, but exhibited significant, albeit weak causal associations with small vessel stroke (SBP: OR 1.04 (1.02-1.06); CAD: OR 1.14 (1.02-1.28)) and large artery stroke (SBP: OR 1.09 (1.06-1.11); CAD: OR 1.59 (1.40-1.79). Conclusions Causality of the association between the cardioembolic stroke subtype and AF is independent from modulators such as SBP and CAD. However, SBP and CAD play a complementary role as causal exposures for small vessel and large artery stroke which in turn are not causally linked with AF.

BackgroundRemnant cholesterol (RC) has been implicated in cardiovascular diseases (CVDs) in populations of European ancestry, yet its causal role remains underexplored in populations of East Asian ancestry, which are underrepresented in genetic studies. We sought to investigate the causal association between circulating RC levels and CVD risk in East Asian populations.MethodsWe first conducted observational analyses of RC and multiple CVD outcomes in Chinese populations. We then conducted genome-wide association studies (GWAS) of RC in 14,939 Chinese individuals and assessed its causal associations with CVD risk using two-sample Mendelian randomization (MR) with Biobank Japan data. Replication analyses in European ancestry populations utilized summary statistics from the UK Biobank and FinnGen.ResultsCirculating RC levels were significantly associated with multiple CVD outcomes in Chinese individuals. Our GWAS identified seven significant loci associated with circulating RC levels in the Chinese population. In the MR analyses, we found that genetically predicted higher RC levels were significantly associated with increased risks of aortic aneurysm (odds ratio per standard deviation increase, 1.82; 95% CI, 1.53–2.17; P = 1.17 × 10−11) and ischemic heart diseases, such as myocardial infarction (1.22, 1.13–1.32; P = 1.81 × 10−7) and stable angina pectoris (1.17, 1.11–1.23; P = 1.18 × 10−8). Notably, these associations persisted after adjustment for total cholesterol, low-density and high-density lipoprotein cholesterols, Apolipoprotein A1 and Apolipoprotein B, respectively. Replication in European ancestry populations confirmed consistent causal effects for aortic aneurysm and ischemic heart diseases. A suggestive East Asian-specific association was identified between genetically predicted higher RC levels and an increased risk of peripheral artery disease, whereas a suggestive association with a higher risk of atrial flutter/fibrillation and ventricular arrhythmia was only observed in populations of European ancestry.ConclusionsOur findings establish RC as an independent causal CVD risk factor in East Asian ancestry individuals and highlight population-specific differences in CVD risk profiles, emphasizing the need for ethnicity-tailored prevention strategies.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12916-025-04329-y.

Genetic analyses of inflammatory polyneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy identified candidate genes

Endometriosis (EMs) and depression are both common conditions that have a significant negative impact on quality of life. However, it is still unclear about the relationship between them. The study was designed to investigate the phenotypic and causal association between depression and EMs. For its nationally representative sample, comprehensive health data and publicly accessibility, we chose data from the National Health and Nutrition Examination Survey for our observational study section including 1393 participants in 2005 to 2006 year cycle which contains information both on depression assessed by the Patient Health Questionnaire 9 and self-reported EMs. Initially, we conducted logistic regression analysis to evaluate phenotypic association between depression and EMs utilizing extensive data taken from National Health and Nutrition Examination Survey. Then, using data from the genome-wide association study (female self-reported depression data: N = 194,153 and female medical-recorded depression data: N = 192,680 from UK Biobank where sex-stratified data was provided; EMs data: N = 150,350 from FinnGen consortium database), we assessed the genetically predicted association performing bidirectional two-sample Mendelian randomization (MR) analysis. Inverse-variance weighted method was employed as the main MR analysis. The Weighted median, MR Egger, Simple mode, Weighted mode, and MR pleiotropy residual sum and outlier test were also performed to assess the robustness of our findings. EMs was present in almost 13.64% of the participants in the depression group, which was much greater than the 6.63% in the non-depression group. Depression and EMs were positively correlated in the observational analysis (OR = 2.44, 95%CI = 1.26–4.74). Furthermore, each greater Patient Health Questionnaire 9 score was associated with a 7% increased risk of EMs. EMs did not have a genetically informed influence on depression, while depression clearly had a genetically predicted effect on EMs, according to bidirectional MR analysis. This study shows a genetically predicted association between depression and EMs as well as a favorable phenotypic correlation. It implies that monitoring of diseases of the reproductive system, such as EMs, in female patients with mood disorders and treating them from a multidisciplinary perspective should not be neglected. Further large-scale prospective cohort studies or mechanistic research are warranted to confirm these results and explore the underlying biological mechanisms.

BackgroundAs the number of COVID-19 deaths continues to rise worldwide, the identification of risk factors for the disease is an urgent issue, and it remains controversial whether atherogenic lipid-related traits including serum apolipoprotein B, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels, are risk factors. The aim of this study was to estimate causal effects of lipid-related traits on COVID-19 risk in the European population using a two-sample Mendelian randomization (MR) approach.MethodsWe used summary statistics from a genome-wide association study (GWAS) that included 441,016 participants from the UK Biobank as the exposure dataset of lipid-related traits and from COVID-19 Host Genetics Initiative GWAS meta-analyses of European ancestry as the outcome dataset for COVID-19 susceptibility (32,494 cases and 1,316,207 controls), hospitalization (8316 cases and 1,549,095 controls), and severity (4792 cases and 1,054,664 controls). We performed two-sample MR analyses using the inverse variance weighted (IVW) method. As sensitivity analyses, the MR-Egger regression, weighted median, and weighted mode methods were conducted as were leave-one-out sensitivity analysis, the MR-PRESSO global test, PhenoScanner searches, and IVW multivariable MR analyses. A P value below 0.0055 with Bonferroni correction was considered statistically significant.ResultsThis MR study suggested that serum apolipoprotein B or LDL-cholesterol levels were not significantly associated with COVID-19 risk. On the other hand, we inferred that higher serum triglyceride levels were suggestively associated with higher risks of COVID-19 susceptibility (odds ratio [OR] per standard deviation increase in lifelong triglyceride levels, 1.065; 95% confidence interval [CI], 1.001–1.13; P = 0.045) and hospitalization (OR, 1.174; 95% CI, 1.04–1.33; P = 0.012), and were significantly associated with COVID-19 severity (OR, 1.274; 95% CI, 1.08–1.50; P = 0.004). Sensitivity and bidirectional MR analyses suggested that horizontal pleiotropy and reverse causation were unlikely.ConclusionsOur MR study indicates a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity in the European population using the latest and largest GWAS datasets to date. However, as the underlying mechanisms remain unclear and our study might be still biased due to possible horizontal pleiotropy, further studies are warranted to validate our findings and investigate underlying mechanisms.

Angina pectoris (AP) is a major factor in heightened risk of cardiac arrest and has been previously linked to sleep patterns. It remains unclear if sleep traits play a role in the onset of AP. Our study aims to declare the causality of sleep traits on AP by Mendelian randomization (MR) analyses. Genome-wide association study (GWAS) data of sleep traits (sleep duration, insomnia, nap during day, chronotype, getting up in morning, narcolepsy, snoring) were obtained from the UK Biobank. The AP datasets came from an analysis containing samples from the UK biobank, FinnGen, and BioBank Japan. The GWAS data of cardiovascular risk factors (hypertension, smoking, hyperlipidemia, type 2 diabetes mellitus (T2DM)) came from the FinnGen. Two-sample MR analyses were carried out to gain a general map of sleep traits, risk factors and AP, then a multivariable MR was performed and the effect of each factor was calculated. We discovered a positive association between nap, narcolepsy, insomnia and stable angina pectoris (SAP), while getting up in morning associated with SAP negatively. Adequate sleep duration related to a reduced risk of SAP and unstable angina pectoris (UAP). Hypertension and T2DM acted as complete mediators in the relationship of nap and SAP, with an effect value of 1.267 (95% CI = 1.178-1.363, P < 0.01) and 1.059 (95% CI = 1.000-1.120, P < 0.05), and the mediating proportion was 27.7% (P < 0.05) and 7.70% (P = 0.102). Our study found that nap, narcolepsy, and insomnia increased the risk of SAP, with hypertension and T2DM mediating the causal relationship between nap and SAP. Getting up in the morning reduced the risk of SAP, while longer sleep duration lowered the risk of SAP and UAP. More evidences are required to clarify the roles of sleep traits and risk factors in AP.

BackgroundPsoriasis is a common, chronic, immune-mediated skin disorder, which is characterized by clearly demarcated areas of erythematous plaques with overlying silvery scales appearing on the skin [1]. Previous studies have...

Nephrotic syndrome, a debilitating manifestation of kidney disease, often arises from diverse glomerular disorders and is accompanied by notable comorbidities. Despite indications of an immunological etiology, the precise role of immune cells in its pathogenesis remains unclear. This study aimed to elucidate the causal relationships between circulating immune cell phenotypes and nephrotic syndrome using a rigorous bidirectional Mendelian randomization approach. We conducted a bidirectional Mendelian randomization analysis leveraging public genome-wide association studies (GWAS) datasets to investigate the causal links between 731 immune cell features and nephrotic syndrome. Our primary analysis employed inverse variance weighting (IVW), complemented by MR-Egger regression, simple model, weighted median method, and weighted model techniques to ensure robustness. Sensitivity analyses were performed to address potential biases arising from heterogeneity, horizontal pleiotropy, and single-nucleotide polymorphism (SNP) instability in nephrotic syndrome. Among traits examined, 13 immune cell phenotypes were identified to have significant causal impacts on nephrotic syndrome (adjusted P > < 0.05). Among these phenotypes, CD25 on unswitched memory B cell, CD25 on memory B cell, CD25 on CD24 + CD27 + B cell, CD25 on IgD-CD38-B cell, CD33dim HLA DR-Absolute Count, and CD127 on granulocyte emerged as causal risk factors, while seven circulating immune cell phenotypes, predominantly monocyte subsets, exhibited protective effects. Furthermore, the reverse Mendelian randomization analysis demonstrated significant effects of nephrotic syndrome on 27 immune phenotypes (P < 0.05). The genetic predictions indicate that multiple circulating immune cell phenotypes, particularly CD25 on specific B-cell subsets, serve as independent risk factors for the onset and progression of nephrotic syndrome. Conversely, monocytes expressing specific phenotypes may exert protective effects against the development of nephrotic syndrome. These findings offer a novel therapeutic approach for the prevention and treatment of nephrotic syndrome.

The association between the length of sleep and atherosclerosis has been reported in many observational studies. However, little is known about its significance as a risk factor for atherosclerosis or as a negative consequence of atherosclerosis. This study aimed to assess the causal association between sleep duration and the risk of atherosclerosis using publicly available genome-wide association studies (GWAS) summary statistics. We employed a two-sample Mendelian randomization (MR) method with 2 cohorts from MRC-IEU (n=460,099) and UK Biobank (n=361,194) to investigate the causal association between sleep duration and the risk of atherosclerosis. Three methods including the inverse-variance weighted (IVW) technique, Robust adjusted profile score (RAPS), and simple-and weighted-median approach were used to obtain reliable results, and an odds ratio with a 95% confidence interval (CI) was calculated. P<0.05 was considered as a statistical difference. In addition, MR-Egger regression, Radial MR, MR-PRESSO, and leave-one-out analyses were used to assess the possible pleiotropy effects. No causal association of sleep duration with atherosclerosis was found [OR (95%CI): 0.90 (0.98-1.00), p = 0.186]. Leave-one-out, MR-Egger, and MR-PRESSO analyses failed to detect horizontal pleiotropy. This MR analysis indicated no causal association between genetically predicted sleep duration and atherosclerosis across European populations.

Modern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors. Here, we propose a two-sample multivariable MR approach based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration.

The causal association between vitamin E status and osteoarthritis (OA) remains controversial in previous epidemiological studies. We employed a Mendelian randomization (MR) analysis to explore the causal relationship between circulating alpha-tocopherol levels (main forms of vitamin E in our body) and OA. The instrumental variables (IVs) of circulating alpha-tocopherol levels were obtained from a Genome-wide association study (GWAS) dataset of 7781 individuals of European descent. The outcome of OA was derived from the UK biobank. Two-sample MR analysis was used to estimate the causal relationship between circulating alpha-tocopherol levels and OA. The inverse-variance weighted (IVW) method was the primary analysis in this analysis. We used the MR-Egger method to determine horizontal pleiotropic in this work. The heterogeneity effect of instrumental IVs was detected by MR-Egger and IVW analyses. Sensitivity analysis was performed by removing single nucleotide polymorphism (SNP) one by one. Three SNPs (rs964184, rs2108622, and rs11057830) (P < 5E−8) strongly associated with circulating alpha-tocopherol levels were used in this analysis. The IVW-random effect indicated no causal relationship between circulating alpha-tocopherol levels and clinically diagnosed OA (OR = 0.880, 95% CI 0.626, 1.236, P = 0.461). Similarly, IVW analysis showed no causal association between circulating alpha-tocopherol levels and self-reported OA (OR = 0.980, 95% CI 0.954, 1.006, P = 0.139). Other methods of MR analyses and sensitivity analyses revealed consistent findings. MR-Egger and IVW methods indicated no significant heterogeneity between IVs. The MR–Egger intercept showed no horizontal pleiotropic. The results of this linear Mendelian randomization study indicate no causal association between genetically predicted alpha-tocopherol levels and the progression of OA. Alpha-tocopherol may not provide beneficial and more favorable outcomes for the progression of OA. Further MR analysis based on updated GWASs with more IVs is required to verify the results of our study.

Frozen shoulder (FS) is a condition that causes shoulder pain and restricted movement, primarily due to inflammation, fibrosis, and adhesion of the shoulder joint capsule. It commonly affects individuals aged 30 to 60 years. Factors such as diabetes, obesity, and shoulder trauma are known risk factors. Although current treatments include nonsteroidal anti-inflammatory drugs, steroid injections, and physical therapy, approximately 22.5% of patients do not respond well to conservative treatments and may require surgical intervention. The ADAMTS family is thought to play a significant role in joint diseases, and this study investigates its impact on FS. This study employed the Mendelian Randomization (MR) analysis method using genome-wide association studies (GWAS) data to analyze the causal relationships between the ADAMTS-5 and ADAMTS-13 genes and FS. By screening SNPs related to ADAMTS-1, ADAMTS-5, and ADAMTS-13, data analysis was performed using R software to verify the impact of these genes on FS pathogenesis. Additionally, co-location analysis was conducted to identify potential therapeutic targets. The MR analysis results indicate that ADAMTS-1-mediated ADAMTS-5 levels, along with the levels of ADAMTS-5 and ADAMTS-13 themselves, significantly increase the risk of FS. Co-expression localization analysis revealed that rs62217270, rs977151, and rs4962153 are potential targets for inhibiting ADAMTS-1, ADAMTS-5, and ADAMTS-13, respectively. In our study, ADAMTS-1, ADAMTS-5, and ADAMTS-13 were identified as potential risk factors contributing to the development of FS. The SNP rs62217270 may serve as a potential therapeutic target for FS by downregulating ADAMTS-5 expression through inhibition of ADAMTS-1. Additionally, rs977151 and rs4962153 were identified as potential targets for FS treatment via the reduction of ADAMTS-5 and ADAMTS-13 levels, respectively.

BackgroundThe causal effects of plasma lipid concentrations and the risk of primary open angle glaucoma (POAG) are still unclear. Thus, the purpose of this study was to identify, applying a two-sample Mendelian randomization (MR) analysis, whether plasma lipid concentrations are causally associated with the risk of POAG.MethodsTwo-sample MR analysis of data from a genome-wide association study (GWAS) was performed to investigate the causal role of plasma lipid levels and POAG. A total of 185 independent single-nucleotide polymorphisms (SNPs) associated with plasma lipid levels were selected as instrumental variables (IVs). The SNPs were obtained from a meta-analysis of GWAS based on 188,577 European-ancestry individuals for MR analyses. Association with POAG for the SNPs was obtained from a GWAS conducted among the United Kingdom (UK) Biobank study participants with a total of 463,010 European-ancestry individuals. Four MR methods (inverse variance weighted [IVW], weighted mode, weighted median, and MR-Egger regression) were applied to obtain the overall causal estimate for multiple, instrumental SNPs.ResultsUsing the IVW analysis method, no evidence was found to support a causal association between plasma LDL-C level and POAG risk (β = − 0.00026; 95% CI = -0.00062, 0.00011; P = 0.165) with no significant heterogeneity among SNPs. The overall causal estimate between plasma LDL-C level and POAG was consistent using the other three MR methods. Using the four MR methods, no evidence of an association between plasma HDL-C (β = 0.00023; 95% CI = -0.00015, 0.00061; P = 0.238; IVW method) or TG levels (β = − 0.00028; 95% CI = -0.00071, 0.00015; P = 0.206; IVW method) and POAG risk was found. Sensitivity analyses did not reveal any sign of directional pleiotropy.ConclusionsThe present study did not find any evidence for a causal association between plasma lipid levels and POAG risk. Further research is needed to elucidate the potential biological mechanisms to provide a reasonable interpretation for these results.