Independent Associations of Education, Intelligence, and Cognition With Hypertension and the Mediating Effects of Cardiometabolic Risk Factors: A Mendelian Randomization Study

Abstract

BACKGROUND: Education, intelligence, and cognition are associated with hypertension, but which one plays the most prominent role in the pathogenesis of hypertension and which modifiable risk factors mediate the causal effects remains unknown. METHODS: Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted 2-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, or cognition on hypertension (FinnGen study, 70 651 cases/223 663 controls; UK Biobank, 77 723 cases/330 366 controls) and blood pressure (International Consortium of Blood Pressure, 757 601 participants), and used 2-step Mendelian randomization to evaluate 25 potential mediators of the association and calculate the mediated proportions. RESULTS: Meta-analysis of inverse variance weighted Mendelian randomization results from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was associated with 44% (95% CI: 0.40–0.79) decreased hypertension risk and 1.682 mm Hg lower systolic and 0.898 mm Hg lower diastolic blood pressure, independently of intelligence and cognition. While the causal effects of intelligence and cognition on hypertension were not independent of education, 6 out of 25 cardiometabolic risk factors were identified as mediators of the association between education and hypertension, ranked by mediated proportions, including body mass index (mediated proportion: 30.1%), waist-to-hip ratio (22.8%), body fat percentage (14.1%), major depression (7.0%), high-density lipoprotein cholesterol (4.7%), and triglycerides (3.4%). These results were robust to sensitivity analyses. CONCLUSIONS: Our findings illustrated the causal, independent impact of education on hypertension and blood pressure and outlined cardiometabolic mediators as priority targets for prevention of hypertension attributable to low education.

Causal impacts of educational attainment on chronic liver diseases and the mediating pathways: Mendelian randomization study

“…In two‐step MR, we examined causal mediators according to the following criteria 14 : (1) there exists a causal association between education and the mediator and the effect of education on the mediator should be unidirectional to ensure the validity of the mediation model; (2) the causal association between the mediator and liver disease persists with adjustment for education; and (3) the association between education and the mediator and the association between the mediator and liver disease should be in opposite directions. In multivariable MR (MVMR) analyses, we selected genetic IVs of the combination of SNPs, which were genome‐wide significant in either the GWAS of education or the GWAS of mediator after clumping summary statistics from GWASs for LD threshold r 2 < 0.001 and distance>10 000 kb.…”

Causal effects of educational attainment on temporomandibular disorders and the mediating pathways: A Mendelian randomization study

“…18 Gaining deeper insights into the intricate relationship between education and health outcomes is instrumental in reducing disparities and enhancing overall population health. 14 A body of observational and MR studies have indicated that higher EA serves as a protective factor against oral diseases. behaviours and a spectrum of other capacities and opportunities that can be harnessed to enhance physical well-being.…”

“…12,13 The random allocation of genetic variants during fertilization, mirroring the principles of randomised controlled trials, substantially diminishes the likelihood of confounding elements, such as sex and age, introducing bias into causal inferences. 14 Additionally, since genotype formation precedes the onset of diseases and is generally impervious to disease progression, the potential for reverse causality is considerably reduced. Recent MR investigations have robustly substantiated the causal relationship between EA and a diverse range of systemic disorders, encompassing hypertension, chronic liver diseases, oropharyngeal cancer and periodontitis.…”

“…Recent MR investigations have robustly substantiated the causal relationship between EA and a diverse range of systemic disorders, encompassing hypertension, chronic liver diseases, oropharyngeal cancer and periodontitis. [14][15][16] Furthermore, multivariable MR (MVMR) has proven instrumental in estimating the intricate pathways through which an exposure affects the outcome, thereby enhancing causal inference in mediating effects. 12,14 Understanding the structure of the potential EA-TMDs relationship is particularly important because modifying the EA is difficult once adulthood is reached.…”

“…[14][15][16] Furthermore, multivariable MR (MVMR) has proven instrumental in estimating the intricate pathways through which an exposure affects the outcome, thereby enhancing causal inference in mediating effects. 12,14 Understanding the structure of the potential EA-TMDs relationship is particularly important because modifying the EA is difficult once adulthood is reached. Thus, we aimed to investigate the causal associations of education with TMDs, with a particular interest in evaluating the mediating effects of modifiable risk factors in the pathogenesis of TMDs to facilitate clinical practice.…”