Multiple Random Effects Research Articles

Causal Effect of Chondroitin, Glucosamine, Vitamin, and Mineral Intake on Kidney Function: A Mendelian Randomization Study.

The causal effects of chondroitin, glucosamine, and vitamin/mineral supplement intake on kidney function remain unknown, despite being commonly used. We conducted a two-sample summary-level Mendelian randomization (MR) analysis to test for causal associations between regular dietary supplement intake and kidney function. Genetic instruments for chondroitin, glucosamine, and vitamin/mineral supplement intake were obtained from a genome-wide association study of European ancestry. Summary statistics for the log-transformed estimated glomerular filtration rate (log-eGFR) were provided by the CKDGen consortium. The multiplicative random-effects inverse-variance weighted method showed that genetically predicted chondroitin and glucosamine intake was causally associated with a lower eGFR (chondroitin, eGFR change beta = -0.113%, standard error (SE) = 0.03%, p-value = 2 × 10-4; glucosamine, eGFR change beta = -0.240%, SE = 0.035%, p-value = 6 × 10-12). However, a genetically predicted vitamin/mineral supplement intake was associated with a higher eGFR (eGFR change beta = 1.426%, SE = 0.136%, p-value = 1 × 10-25). Validation analyses and pleiotropy-robust MR results for chondroitin and vitamin/mineral supplement intake supported the main results. Our MR study suggests a potential causal effect of chondroitin and glucosamine intake on kidney function. Therefore, clinicians should carefully monitor their long-term effects.

The long-term mediation role of cytokines on the causal pathway from maternal gestational age to offspring eye diseases: Lifecourse-Network Mendelian randomization

BackgroundGestational duration has a significant impact on eye diseases. A large number of evidences suggest that cytokines are associated with gestational duration and eye diseases. However, the causal relationships among cytokines, maternal gestational impairment and offspring eye diseases remain unclear. MethodsWe performed lifecourse-network Mendelian randomization (MR) to explore the causal relationships between maternal gestational duration (from the Early Growth Genetics (EGG) Consortium and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study, N = 84,689), neonatal/adult cytokines (from the NHGRI-EBI Catalog, N = 764/4,618), and adult eye diseases (from FinnGen consotium, N = 309,154) using summary-level data from large genome-wide association studies. Multiplicative random effects inverse variance weighted (IVW) and multivariable-IVW methods were the main analysis methods, and the other 15 pleiotropy-robust methods, weak IV-robust methods, and outliers-robust methods were used as auxiliary methods. ResultsMaternal gestational age (early preterm birth, preterm birth, gestational duration, and post-term birth) had a causal relationship with 42 eye diseases. Four neonatal cytokines, Tumor Necrosis Factor-α(TNF-α), IL10, GROA, and CTACK, as well as four adult cytokines, CTACK, IL10, IL12p70 and IL6 are mediators in the causal relationships between early preterm birth and preterm birth in eight eye diseases. However, after adjusting for these mediators, a null direct causal effect of early preterm birth and preterm birth on eight eye diseases was found. In addition, there was no mediator in the causal relationship between gestational duration and post-term birth to eye diseases. ConclusionThe effects of maternal gestational duration on offspring eye diseases through cytokines are long-term and life-course effects.

Mendelian randomization uncovers a protective effect of interleukin-1 receptor antagonist on kidney function

Interleukins (ILs), key cytokine family of inflammatory response, are closely associated with kidney function. However, the causal effect of various ILs on kidney function needs further investigation. Here we show two-sample summary-level Mendelian randomization (MR) analysis that examined the causality between serum IL levels and kidney function. Genetic variants with strong association with serum IL levels were obtained from a previous genome-wide association study meta-analysis. Summary-level data for estimated glomerular filtration rate (eGFR) were obtained from CKDGen database. As a main MR analysis, multiplicative random-effects inverse-variance weighted method was performed. Pleiotropy-robust MR analysis, including MR-Egger with bootstrapped error and weighted median methods, were also implemented. We tested the causal estimates from nine ILs on eGFR traits. Among the results, higher genetically predicted serum IL-1 receptor antagonist level was significantly associated with higher eGFR values in the meta-analysis of CKDGen and the UK Biobank data. In addition, the result was consistent towards eGFR decline phenotype of the outcome database. Otherwise, nonsignificant association was identified between other genetically predicted ILs and eGFR outcome. These findings support the clinical importance of IL-1 receptor antagonist-associated pathway in relation to kidney function in the general individuals, particularly highlighting the importance of IL-1 receptor antagonist.

Thyroid Function and Metabolic Syndrome: A Two-Sample Bidirectional Mendelian Randomization Study.

Thyroid function has been associated with metabolic syndrome (MetS) in a number of observational studies but the direction of effects and the exact causal mechanism of this relationship is still unknown. To examine genetically predicted effects of thyroid function on MetS risk and its components, and vice versa, using large-scale summary genetic association data. We performed a two-sample bidirectional Mendelian randomization (MR) study using summary statistics from the most comprehensive genome-wide association studies (GWAS) of thyroid-stimulating hormone (TSH, n = 119 715), free thyroxine (fT4, n = 49 269), MetS (n = 291 107), and components of MetS: waist circumference (n = 462 166), fasting blood glucose (n = 281 416), hypertension (n = 463 010), triglycerides (TG, n = 441 016) and high-density lipoprotein cholesterol (HDL-C, n = 403 943). We chose the multiplicative random effects inverse variance weighted (IVW) method as the main analysis. Sensitivity analysis included weighted median and mode analysis, as well as MR-Egger and Causal Analysis Using Summary Effect estimates (CAUSE). Our results suggest that higher fT4 levels lower the risk of developing MetS (OR = 0.96, P = .037). Genetically predicted fT4 was also positively associated with HDL-C (β = 0.02, P = .008), while genetically predicted TSH was positively associated with TG (β = 0.01, P = .044). These effects were consistent across different MR analyses and confirmed with the CAUSE analysis. In the reverse direction MR analysis, genetically predicted HDL-C was negatively associated with TSH (β = -0.03, P = .046) in the main IVW analysis. Our study suggests that variations in normal-range thyroid function are causally associated with the diagnosis of MetS and with lipid profile, while in the reverse direction, HDL-C has a plausible causal effect on reference-range TSH levels.

Smoothed simulated pseudo-maximum likelihood estimation for nonlinear mixed effects models with censored responses.

Nonlinear mixed effects models have been widely applied to analyses of data that arise from biological, agricultural, and environmental sciences. Estimation of and inference on parameters in nonlinear mixed effects models are often based on the specification of a likelihood function. Maximizing this likelihood function can be complicated by the specification of the random effects distribution, especially in the presence of multiple random effects. The implementation of nonlinear mixed effects models can be further complicated by left-censored responses, representing measurements from bioassays where the exact quantification below a certain threshold is not possible. Motivated by the need to characterize the nonlinear human immunodeficiency virus RNA viral load trajectories after the interruption of antiretroviral therapy, we propose a smoothed simulated pseudo-maximum likelihood estimation approach to fit nonlinear mixed effects models in the presence of left-censored observations. We establish the consistency and asymptotic normality of the resulting estimators. We develop testing procedures for the correlation among random effects and for testing the distributional assumptions on random effects against a specific alternative. In contrast to the existing variants of expectation-maximization approaches, the proposed methods offer flexibility in the specification of the random effects distribution and convenience in making inference about higher-order correlation parameters. We evaluate the finite-sample performance of the proposed methods through extensive simulation studies and illustrate them on a combined dataset from six AIDS Clinical Trials Group treatment interruption studies.

#3819 THE PROTECTIVE EFFECT OF INTERLEUKIN-1 RECEPTOR ANTAGONIST ON KIDNEY FUNCTION: A MENDELIAN RANDOMIZATION STUDY

Abstract Background and Aims Interleukins (ILs), key cytokine family of inflammatory response, are closely associated with kidney function. However, the causal effect of various ILs on kidney function needs further investigation. Method We performed two-sample summary-level mendelian randomization (MR) analysis (Fig. 1). Genetic variants with strong association with serum IL levels were obtained from a previous genome-wide association study meta-analysis. Summary-level data for eGFR were obtained from CKDGen database. A replication analysis was performed in the independent UK Biobank data. As a main MR analysis, multiplicative random-effect inverse-variance weighed method was performed. Pleiotropy-robust MR analysis, including MR-Egger with bootstrapped error and weighed-median methods, were also implemented. Results We tested the causal estimates from nine ILs on eGFR traits. Among ILs, we found that genetically predicted serum IL-1ra level showed consistently significant association (P <0.05) with eGFR, also supported by significant (P <0.05) pleiotropy-robust MR results. Using 20 SNPs (18 of pQTL and 2 of eQTL SNPs), genetically predicted higher serum IL-1ra level was significantly associated (<0.05) with higher eGFR in multiplicative random effect IVW analysis (Fig. 2). In addition, the result was consistent towards eGFR decline phenotype of the outcome database. Otherwise, nonsignificant association was identified between other genetically predicted ILs and eGFR outcome (Fig. 3). Conclusion These findings support the clinical importance of IL-1 associated pathway in relation to kidney function in the general individuals, particularly highlighting the importance of IL-1ra.

#6774 CAUSAL ASSOCIATION OF COVID-19 AND KIDNEY FUNCTION: A MENDELIAN RANDOMIZATION ANALYSIS

Abstract Background and Aims Previous observational studies suggest that there are potential relationships between COVID-19 and kidney functions. However, whether COVID-19 had causal effects on different kidney traits is currently unclear. We aimed to investigate the causal link between genetically determined COVID-19 and following kidney traits. Method We performed univariate Mendelian randomization (MR) studies using summary genome-wide association studies (GWAS) statistics of COVID-19 severity (n case/n control: 13,769/1,072,442 for European, n case/n control: 794/4862 for Asian), COVID-19 hospitalization (n case/n control: 32,519/2,062,805 for European, n case/n control:2882/31,200 for Asian) and COVID-19 susceptibility (n case/n control: 122,616/2,475,240 for European, n case/n control: 4459/36,121 for Asian) derived from THE COVID-19 Host Genetics Initiative (r7) as exposure. Phenotypic outcomes analyzed for Europeans included chronic kidney disease (CKD), creatinine-based estimated glomerular filtration rate, Cystatin C-based estimated glomerular filtration rate, Urine albumin-to-creatinine ratio, acute and chronic glomerulonephritis, membranous nephropathy, diabetic nephropathy, acute and chronic nephritic syndrome, acute renal failure, glomerular diseases and IgA nephropathy. While for Asians, outcomes including CKD, estimated glomerular filtration rate, serum creatinine, acute and chronic renal failure, diabetic nephropathy, IgA nephropathy, nephrotic syndrome, acute and chronic glomerulonephritis as well as membranous nephropathy were analyzed. The inverse variance weighted (IVW) MR with multiplicative random effects model was performed as primary analysis to evaluate the causal effects of COVID-19 on different kidney traits, and potential pleiotropy as well as heterogeneity was evaluated by using MR Egger and heterogeneity test, respectively. A series of sensitivity analyses, including weighted median MR, weighted mode MR, MR Pleiotropy Residual Sum and Outlier (MR PRESSO) were performed. In addition, the causal effects of COVID-19 on different kidney traits were validated by using additional GWAS summary data of critical COVID-19 (n case/n control: 5989/42891 for European, n case/n control: 274/366 for Asian) from GenOMICC database (r6) as exposure. After multiple corrections, a P value < 0.0036 for Europeans and P value < 0.0045 for Asians were considered as significant. Results IVW MR indicated that none of the COVID-19 phenotypes were associated with CKD (OR, 0.99: P = 0.16 for COVID-19 severity; OR, 0.99: P = 0.41 for COVID-19 hospitalization; OR, 0.95: P = 0.26 for COVID-19 susceptibility), nor other kidney traits for Europeans. As for Asian ancestry, consistent with the findings in Europeans, none of the COVID-19 phenotypes were associated with CKD (OR, 0.89: P = 0.16 for COVID-19 severity; OR, 0.93: P = 0.42 for COVID-19 hospitalization; OR, 0.95: P = 0.61 for COVID-19 susceptibility), nor other kidney traits as mentioned above. All sensitivity analyses also consistently indicated the absence of causal effects of COVID-19 severity, hospitalization and susceptibility on different kidney traits, neither in the European nor in the Asian population. Conclusion There is no significant evidence supporting the causal effects of genetically predicted COVID-19 phenotype on the following different kidney traits. More deeply explorations focused on the association between COVID-19 and kidney traits should be performed with more data would be available in the future.

A Simulation Study on Cross-classified Multiple Membership Random Effects Modeling Estimation

본 모의실험 연구에서는 잔차의 비정규성이 교차분류 다중소속 무선효과 모형 모수추정에 어떠한 영향을 미치는지 살펴보고자 하였다. 이를 위해 잔차 분포(정규 분포, 균일 분포 및 카이제곱 분포), 집단 내 상관 계수(0.1, 0.2 및 0.3), 집단 수(20, 50 및 100), 집단 크기(10 및 20), 교차분류 비율(20% 및 40%), 다중소속 비율(10% 및 20%) 조건이 고려되었다. 다양한 조건 하에서 교차분류 다중소속 무선효과 모형 추정 시 상대편의와 평균제곱근오차를 확인하였다. 분석 결과, 잔차의 비정규성은 특히나 집단 수가 상대적으로 작고 (즉, 50 이하일 때), 집단 내 상관계수가 커질 때, 교차분류와 2 수준에서 다중소속이 발생한 임의효과 분산 추정에 더 큰 영향을 미치는 것으로 나타났다. 또한 2 수준 잔차의 분포가 균일 분포(즉, 비정규적이나 대칭적인 분포)에 비해 카이제곱 분포(즉, 심하게 치우친 분포)일 때 상대편의성이 커지는 것으로 나타났다. 95% 신용구간의 경우 카이제곱 분포를 적용하였을 때 명목수준 보다 작게 나타난 반면, 균일 분포를 적용한 경우에는 명목수준보다 크게 나타났다. 본 연구결과는 교차분류와 상위수준에서 다중소속이 발생하는 다층자료의 맥락효과를 분석하기 위해 교차분류 다중소속 다층모형을 적용하는 데 있어 유용한 정보를 제공할 것으로 기대한다.This simulation study investigated how residual non-normality affects cross-classified multiple membership random effects modeling estimates. The conditions manipulated in the study were residual distribution type (normal, uniform, and chi-squared), intra-unit correlation coefficients (0.1, 0.2, and 0.3), number of groups (20, 50, and 100), average group size (10 and 20), cross-classification rate (20% and 40%), and multiple membership rate (10% and 20%). The relative bias and the root mean square of the parameter estimates were evaluated. The results indicated that non-normal residuals had a larger impact on the cross-classified multiple membership random effect variance component estimates, especially when the number of groups was relatively smaller (i.e., 50 groups or less) and that the intra-unit correlation coefficient increased. Specifically, the degrees of relative bias were larger when the level-two residuals followed chi-squared distribution (i.e., a severely skewed distribution) compared to uniform distribution (i.e., a non-normal but symmetrical distribution). The coverage rates of the level-two variance component were lower than the nominal 95% when residuals followed chi-squared distribution, while they were higher when residuals followed uniform distribution. These findings can be useful in applying cross-classified multiple membership random effects modeling to account for the contextual effects of cross-classified and multiple higher-level units.

Stochastic EM Algorithm for Joint Model of Logistic Regression and Mechanistic Nonlinear Model in Longitudinal Studies

We study a joint model where logistic regression is applied to binary longitudinal data with a mismeasured time-varying covariate that is modeled using a mechanistic nonlinear model. Multiple random effects are necessary to characterize the trajectories of the covariate and the response variable, leading to a high dimensional integral in the likelihood. To account for the computational challenge, we propose a stochastic expectation-maximization (StEM) algorithm with a Gibbs sampler coupled with Metropolis–Hastings sampling for the inference. In contrast with previous developments, this algorithm uses single imputation of the missing data during the Monte Carlo procedure, substantially increasing the computing speed. Through simulation, we assess the algorithm’s convergence and compare the algorithm with more classical approaches for handling measurement errors. We also conduct a real-world data analysis to gain insights into the association between CD4 count and viral load during HIV treatment.

Effect of basal metabolic rate on lifespan: a sex-specific Mendelian randomization study

Observationally, the association of basal metabolic rate (BMR) with mortality is mixed, although some ageing theories suggest that higher BMR should reduce lifespan. It remains unclear whether a causal association exists. In this one-sample Mendelian randomization study, we aimed to estimate the casual effect of BMR on parental attained age, a proxy for lifespan, using two-sample Mendelian randomization methods. We obtained genetic variants strongly (p-value < 5 × 10–8) and independently (r2 < 0.001) predicting BMR from the UK Biobank and applied them to a genome-wide association study of parental attained age based on the UK Biobank. We meta-analyzed genetic variant-specific Wald ratios using inverse-variance weighting with multiplicative random effects by sex, supplemented by sensitivity analysis. A total of 178 and 180 genetic variants predicting BMR in men and women were available for father’s and mother’s attained age, respectively. Genetically predicted BMR was inversely associated with father’s and mother’s attained age (years of life lost per unit increase in effect size of genetically predicted BMR, 0.46 and 1.36; 95% confidence interval 0.07–0.85 and 0.89–1.82), with a stronger association in women than men. In conclusion, higher BMR might reduce lifespan. The underlying pathways linking to major causes of death and relevant interventions warrant further investigation.

Appraising the Associations Between Systemic Iron Status and Epigenetic Clocks: A Genetic Correlation and Bidirectional Mendelian Randomization Study

BackgroundGenetic correlations (Rg) and bidirectional causal effects between systemic iron status and epigenetic clocks have not been fully investigated, although observational studies have suggested systemic iron status is associated with human aging. ObjectivesWe explored the genetic correlations and bidirectional causal effects between systemic iron status and epigenetic clocks. MethodsLeveraging large-scale genome-wide association study summary-level statistics for 4 systemic iron status biomarkers (ferritin, serum iron, transferrin, and transferrin saturation) (N = 48,972) and 4 measures for epigenetic age (GrimAge, PhenoAge, intrinsic epigenetic age acceleration (IEAA), and HannumAge) (N = 34,710), genetic correlations, and bidirectional causal effects were estimated between them mainly by applying linkage disequilibrium score (LDSC) regression, Mendelian randomization (MR), and MR based on Bayesian model averaging. The main analyses were conducted employing multiplicative random-effects inverse-variance weighted MR. MR-Egger, weighted median, weighted mode, and MR-PRESSO were performed as sensitivity analyses to support the robustness of causal effects. ResultsThe LDSC results illustrated Rg between serum iron and PhenoAge (Rg = 0.1971, P = 0.048) and between transferrin saturation and PhenoAge (Rg = 0.196, P = 0.0469). We found that increased ferritin and transferrin saturation significantly increased all 4 measures of epigenetic age acceleration (all P < 0.0125, β > 0). Each standard deviation genetically increases in serum iron only significantly associated with increased IEAA (β: 0.36; 95% CI: 0.16, 0.57; P = 6.01 × 10−4) and increased HannumAge acceleration (β: 0.32; 95% CI: 0.11, 0.52; P = 2.69 × 10−3). Evidence showed a suggestively significant causal effect of transferrin on epigenetic age acceleration (all 0.0125 <P < 0.05). Additionally, reverse MR study indicated no significant causal effect of epigenetic clocks on systemic iron status. ConclusionsAll 4 iron status biomarkers had a significant or suggestively significant causal effect on epigenetic clocks, whereas reverse MR studies did not.

Assessing the role of lipid-lowering therapy on multi-cancer prevention: A mendelian randomization study.

Background: Statin use for cancer prevention has raised wide attention but the conclusions are still controversial. Whether statins use have exact causal effects on cancer prevention remains unclear. Methods: Based on the Genome-Wide Association Studies (GWAS) datasets from the large prospective UK Biobank and other consortium databases, two-sample mendelian randomization (MR) analysis was conducted to explore the causal effects of statins use on varied site-specific cancer risks. Five MR methods were applied to investigate the causality. The stability, heterogeneity, and pleiotropy of MR results were also evaluated. Results: The atorvastatin use could increase the risk of colorectal cancer (odd ratio (OR) = 1.041, p = 0.035 by fixed-effects inverse variance weighted (IVW) method (IVWFE), OR = 1.086, p = 0.005 by weighted median; OR = 1.101, p = 0.048 by weighted mode, respectively). According to the weighted median and weighted mode, atorvastatin could modestly decrease the risk of liver cell cancer (OR = 0.989, p = 0.049, and OR = 0.984, p = 0.004, respectively) and head and neck cancer (OR = 0.972, p = 0.020). Besides, rosuvastatin use could reduce the bile duct cancer risk by 5.2% via IVWEF method (OR = 0.948, p = 0.031). No significant causality was determined in simvastatin use and pan-cancers via the IVWFE or multiplicative random-effects IVW (IVWMRE) method if applicable (p > 0.05). There was no horizontal pleiotropy observed in the MR analysis and the leave-one-out analysis proved the stability of the results. Conclusion: The causalities between statin use and cancer risk were only observed in colorectal cancer and bile duct cancer in the European ancestry population. Future works are warranted to provide more robust evidence for supporting statin repurposing for cancer prevention.

Reasons for admission to service and overrepresentation of Black youth in the child welfare system in Ontario, Canada: Does race matter?

BackgroundIn studies exploring racial disparities in the Canadian child welfare systems, evidence is still lacking on the reasons for admission of children to service. ObjectiveThis study investigates the reasons for admission to service in Ontario child welfare based on racial identities. MethodsWe analyzed three-time points (2018, 2019, and 2020) of the Ontario Looking After Children (OnLAC) project. The sample included 4036 children (Mage = 14.30, SD = 2.21; 39.22 % girls). Univariate and multiple random-effects (REs) logistic regressions were performed to analyze the admission to service according to racial identities. ResultsThe results showed that the most frequent reason for admission to service was caregiver capacity in 2018 (56.02 %), 2019 (57.76 %), and 2020 (55.49 %). The results revealed few differences between racial groups on the reasons for their admission to service. There were more differences between racial groups in 2019 and 2020. The three-year cohort analyses showed that Black youth were less likely to have admission to service due to harm by omission (AOR = 0.41, 95%CI 0.18–0.93, z = −2.14, p < .05) and emotional harm (AOR = 0.40, 95%CI 0.17–0.92, z = −2.12, p < .05) than other racial groups. Results from the multiple random-effects logistic regression showed that in 2019 (AOR = 1.83, 95%CI 1.28–2.62, z = 3.32, p < .01) and 2020 (AOR = 2.13, 95%CI 1.41–3.21, z = 3.58, p < .01), youth were particularly at risk of having been admitted to service for caregiver capacity. ConclusionsThe present study reveals a comprehensive description of the reasons for admission in child welfare in Ontario according to racial identities. Implications for research, prevention, and intervention are discussed.

The Causality between Diabetes and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

Diabetes was considered as a risk factor for venous thromboembolism (VTE), but conflicting findings have been reported from observational studies. This study aimed at investigating the causal associations of type 1 and type 2 diabetes with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). We designed a bidirectional two-sample Mendelian randomization (MR) analysis by using summary-level data from large genome-wide association studies performed in European individuals. Inverse variance weighting with multiplicative random effect method was used to obtain the primary causal estimates, and weighted median, weighted mode, and MR egger regression were replenished as sensitivity analyses to test the robustness of the results. We found no significant causal effects of type 1 diabetes on VTE (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.96-1.00, p = 0.043), DVT (OR: 0.98, 95% CI: 0.95-1.00, p = 0.102), and PE (OR: 0.98, 95% CI: 0.96-1.01, p = 0.160). Similarly, no significant associations of type 2 diabetes with VTE (OR: 0.97, 95% CI: 0.91-1.03, p = 0.291), DVT (OR: 0.96, 95% CI: 0.89-1.03, p = 0.255), and PE (OR: 0.97, 95% CI: 0.90-1.04, p = 0.358) were also observed. Results from multivariable MR analysis were consistent with the findings in univariable analysis. In the other direction, the results showed no significant causal effects of VTE on type 1 and type 2 diabetes. This MR analysis demonstrated no significant causal associations of type 1 and type 2 diabetes with VTE in both directions, in conflict with previous observational studies reporting positive association, which provided clues for understanding the underlying pathogenesis of diabetes and VTE.

Genetic liability to mental disorders in relation to the risk of hypertension.

Observational studies have indicated that psychosocial factors contribute to hypertension; however, the causality of these associations remains unclear due to reverse causality and confounders. We aim to assess the causal associations of mental health disorders with hypertension. Instrumental variables of anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, depression, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, and subjective well-being measure were obtained from the corresponding largest genome-wide association studies. Summary statistics for the association of essential hypertension were obtained from the FinnGen Study (42,857 cases and 162,837 controls) and UK Biobank cohort (54,358 cases and 408,652 controls). The multiplicative random-effects inverse-variance weighted method was utilized as the primary analysis and three other statistical methods were conducted in the supplementary analyses. The results were combined using the fixed-effects method. In the pooled analyses, genetic liability to depression was associated with higher risk of hypertension (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.17-1.35; p < 0.001). Besides, a suggestive association was found between genetically predicted higher weighted neuroticism sum-score and increased risk of hypertension (OR, 1.16; 95% CI, 1.02-1.33; p < 0.05). No associations were found for other mental health disorders. Sensitivity analyses revealed consistent evidence as the main results. We provide consistent evidence for the causal effect of genetic liability to depression on hypertension, which highlights the importance of blood pressure measurement and monitoring in patients with depression.

Causal relationship between moderate to vigorous physical activity and venous thromboembolism.

Previous studies have shown conflicting results about the impact of moderate to vigorous physical activity on the risk of venous thromboembolism (VTE). Using Mendelian randomization, we assessed whether moderate to vigorous physical activity causally affects VTE from genetic level. Genetic instruments associated with moderate to vigorous physical activity at the genome-wide significance level (P < 5×10- 8) were selected from the UK Biobank. Summary-level data for VTE were obtained from the FinnGen consortium. Univariable and multivariable Mendelian randomization analyses were conducted. Genetically predicted moderate to vigorous physical activity had no effect on VTE [odds ratio (OR) = 1.08; 95% confidence interval (CI) 0.66-1.78; P = 0.75] under a multiplicative random-effects inverse-variance weighted model. MR-Egger (OR = 0.20; 95% CI 0.01-4.70; P = 0.33), weighted median (OR = 1.08; 95% CI 0.52-2.25; P = 0.84), simple mode (OR = 2.53; 95% CI 0.59-10.92; P = 0.23), weighted mode (OR = 2.21; 95% CI 0.50-9.74; P = 0.31), and multivariable Mendelian randomization (OR = 0.74; 95% CI 0.46-1.19; P = 0.22) also yielded no significant association. The overall estimate was not influenced by individual single nucleotide polymorphism. No evidence of heterogeneity or horizontal pleiotropy was observed. Therefore, moderate to vigorous physical activity had no causal association with VTE in the general population.

Age at menarche and ischemic heart disease: An update mendelian randomization study.

Background: Although earlier menarche age has been associated with ischemic heart disease in previous observational studies, the relationship's causation has not been shown. Through two-sample Mendelian randomization (MR), we were able to define the causal connection. Methods: We performed Mendelian Randomization (MR) analysis to explore the associations between genetically predicted AAM and IHD. Summary-level databases for exposure and outcome were selected from the MR-Base database (https://gwas.mrcieu.ac.uk/). Single-nucleotide polymorphisms (SNPs) connected to AAM at genome-wide significance level (p < 5 × 10-8) were considered as instrumental variables (IVs). We used four methods to pool MR estimates, including fixed-effects inverse variance weighting (fe-IVW), multiplicative random-effects inverse variance weighting (mre-IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses were performed to evaluate the robustness of the results. PhenoScanner searches and Multivariable Mendelian randomization (MVMR) analysis was used for assessing confounders. Results: 117 SNPs significantly correlated with AAM were screened as instruments, the results of three main methods showed that genetically earlier AAM may have a causal effect on the higher risk of IHD (fe-IVW: OR = 0.80, 95% CI: 0.72-0.88, p < 0.001; mre-IVW: OR = 0.80, 95% CI: 0.70-0.90, p < 0.001; WE: OR = 0.79, 95% CI: 0.66-0.93, p = 0.006). These results were consistent across sensitivity analyses. MR analysis revealed that there was still a relationship between AAM and IHD even when pleiotropic SNPs of confounders were removed employing PhenoScanner searches. In MVMR, the significant association remained after adjusting for biological sex, but it was attenuated with adjustment of body mass index including childhood and adult. Conclusion: Our MR analysis revealed a substantial genetically determined confounder-mediated relationship between an increase in genetically predicted AAM and a lower risk of IHD. By addressing the intervention of body mass index, the risk of IHD may be lowered.

Estimating interactions in individual participant data meta-analysis: a comparison of methods in practice

Medical interventions may be more effective in some types of individuals than others and identifying characteristics that modify the effectiveness of an intervention is a cornerstone of precision or stratified medicine. The opportunity for detailed examination of treatment-covariate interactions can be an important driver for undertaking an individual participant data (IPD) meta-analysis, rather than a meta-analysis using aggregate data. A number of recent modelling approaches are available. We apply these methods to the Perinatal Antiplatelet Review of International Studies (PARIS) Collaboration IPD dataset and compare estimates between them. We discuss the practical implications of applying these methods, which may be of interest to aid meta-analysists in the use of these, often complex models.Models compared included the two-stage meta-analysis of interaction terms and one-stage models which fit multiple random effects and separate within and between trial information. Models were fitted for nine covariates and five binary outcomes and results compared.Interaction terms produced by the methods were generally consistent. We show that where data are sparse and there is low heterogeneity in the covariate distributions across trials, the meta-analysis of interactions may produce unstable estimates and have issues with convergence. In this IPD dataset, varying assumptions by using multiple random effects in one-stage models or using only within trial information made little difference to the estimates of treatment-covariate interaction. Method choice will depend on datasets characteristics and individual preference.

Association between dried fruit intake and pan-cancers incidence risk: A two-sample Mendelian randomization study.

BackgroundObservational studies have revealed that dried fruit intake may be associated with cancer incidence; however, confounding factors make the results prone to be disturbed. Therefore, we conducted a two-sample Mendelian randomization (MR) study to explore the causal relationship between dried fruit intake and 11 site-specific cancers.Materials and methodsForty-three single nucleoside polymers (SNPs) with robust genome-wide association study (GWAS) evidence, strongly correlated with dried fruit intake, were used as instrumental variables (IVs) in this study. The summary-level genetic datasets of site-specific cancers were obtained from the Oncoarray oral cavity and oropharyngeal cancer consortium, International Lung Cancer Consortium, Breast Cancer Association Consortium (BCAC), Ovarian Cancer Association Consortium, PanScan1, and GWAS of other scholars. We analyzed the causality between dried fruit intake and 11 site-specific cancers using the inverse-variance-weighted (IVW) and weighted median (WM) methods. For the results of the MR analysis, Cochran’s Q test was used to check for heterogeneity, and multiplicative random effects were used to evaluate the heterogeneity further. Gene pleiotropy was tested using MR-Egger regression and MR-PRESSO methods. In addition, the main results of this study were validated by using the summary statistical data from the FinnGen and UK Biobank databases, and adjusted body mass index (BMI), years of education, fresh fruit intake, and vitamin C using multivariable MR analysis to ensure the stability of the research results.ResultsThe evidence from IVW analyses showed that each increase of dried fruit intake by one standard deviation was statistically significantly associated with 82.68% decrease of oral cavity/pharyngeal cancer incidence risk (P = 0.0131), 67.01% decrease of lung cancer incidence risk (P = 0.0011), 77% decrease of squamous cell lung cancer incidence risk (P = 0.0026), 53.07% decrease of breast cancer incidence risk (P = 4.62 × 10–5), 39.72% decrease of ovarian cancer incidence risk (P = 0.0183), 97.26% decrease of pancreatic cancer incidence risk (P = 0.0280), 0.53% decrease of cervical cancer incidence risk (P = 0.0482); however, there was no significant effect on lung adenocarcinoma (P = 0.4343), endometrial cancer (P = 0.8742), thyroid cancer (P = 0.6352), prostate cancer (P = 0.5354), bladder cancer (P = 0.8996), and brain cancer (P = 0.8164). In the validation part of the study results, the causal relationship between dried fruit intake and lung cancer (P = 0.0043), squamous cell lung cancer (P = 0.0136), and breast cancer (P = 0.0192) was determined. After adjusting for the potential impact of confounders, the causal relationship between dried fruit intake and lung cancer (P = 0.0034), squamous cell lung cancer (P = 0.046), and breast cancer (P = 0.0001) remained. The sensitivity analysis showed that our results were stable and reliable.ConclusionThe intake of dried fruits may have a protective effect against some site-specific cancers. Therefore, health education and a reasonable adjustment of dietary proportions may help in the primary prevention of cancer.

Implicating Causal Brain Magnetic Resonance Imaging in Glaucoma Using Mendelian Randomization.

BackgroundGlaucoma is hypothesized to originate in the brain but manifests as an eye disease as it possesses the common features of neurodegeneration diseases. But there is no evidence to demonstrate the primary brain changes in glaucoma patients. In the present study, we have used Mendelian randomization (MR) to understand the causal effect of brain alterations on glaucoma.MethodsOur MR study was carried out using summary statistics from genome-wide associations for 110 diffusion tensor imaging (DTI) measurements of white matter (WM) tracts (17,706 individuals), 101 brain region-of-interest (ROI) volumes (19,629 individuals), and glaucoma (8,591 cases, 210,201 control subjects). The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method and verified by two other MR methods, including MR Egger, weighted median, and extensive sensitivity analyses.ResultsGenetic liability to fornix fractional anisotropy (FX.FA) (OR = 0.71, 95%CI = 0.56–0.88, P = 2.44 × 10–3), and uncinate fasciculus UNC.FA (OR = 0.65, 95%CI = 0.48–0.88, P = 5.57 × 10–3) was associated with a low risk of glaucoma. Besides, the right ventral diencephalon (OR = 1.72, 95%CI = 1.17–2.52, P = 5.64 × 10–3) and brain stem (OR = 1.35, 95%CI = 1.08–1.69, P = 8.94 × 10–3) were associated with the increased risk of glaucoma. No heterogeneity and pleiotropy were detected.ConclusionOur study suggests that the fornix and uncinate fasciculus degenerations and injures of the right ventral diencephalon and brain stem potentially increase the occurrence of glaucoma and reveal the existence of the brain-eye axis.