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

BACKGROUND AND AIMS: Educational attainment is an essential socio-economic indicator with broad implications for lifestyle behaviour and metabolic health. We aimed to investigate the causal effect of education on chronic liver diseases and the potential mediating pathways. METHODS: We applied univariable Mendelian randomization (MR) to assess the causal associations between educational attainment and non-alcoholic fatty liver disease (NAFLD) (cases/controls: 1578/307 576 in FinnGen; 1664/400 055 in UK Biobank), viral hepatitis (1772/307 382; 1215/403 316), hepatomegaly (199/222 728; 297/400 055), chronic hepatitis (699/301 014; 277/403 316), cirrhosis (1362/301 014; 114/400 055) and liver cancer (518/308 636; 344/393 372) using summary statistics of genome-wide association studies from the FinnGen Study and the UK Biobank, respectively. We used two-step MR to evaluate potential mediators and their mediation proportions in the association. RESULTS: Meta-analysis of inverse variance weighted MR estimates from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was causally associated with decreased risks of NAFLD (OR: 0.48; 95%CI: 0.37-0.62), viral hepatitis (0.54; 0.42-0.69) and chronic hepatitis (0.50; 0.32-0.79), but not hepatomegaly, cirrhosis and liver cancer. Nine, two and three out of 34 modifiable factors were identified as causal mediators in the associations of education with NAFLD, viral hepatitis and chronic hepatitis, respectively, including six adiposity traits (mediation proportion: 16.5%-32.0%), major depression (16.9%), two glucose metabolism-related traits (2.2%-15.8%) and two lipids (9.9%-12.1%). CONCLUSIONS: Our findings supported the causal protective effects of education on chronic liver diseases and outlined mediating pathways to inform prevention and intervention strategies to reduce the burden of liver diseases, especially for individuals with lower education.

Mendelian randomization evidence for the causal effects of socio-economic inequality on human longevity among Europeans.

Human longevity correlates with socio-economic status, and there is evidence that educational attainment increases human lifespan. However, to inform meaningful health policies, we need fine-grained causal evidence on which dimensions of socio-economic status affect longevity and the mediating roles of modifiable factors such as lifestyle and disease. Here we performed two-sample Mendelian randomization analyses applying genetic instruments of education, income and occupation (n = 248,847 to 1,131,881) to estimate their causal effects and consequences on parental lifespan and self-longevity (n = 28,967 to 1,012,240) from the largest available genome-wide association studies in populations of European ancestry. Each 4.20 years of additional educational attainment were causally associated with a 3.23-year-longer parental lifespan independently of income and occupation and were causally associated with 30-59% higher odds of self-longevity, suggesting that education was the primary determinant. By contrast, each one-standard-deviation-higher income and one-point-higher occupation was causally associated with 3.06-year-longer and 1.29-year-longer parental lifespans, respectively, but not independently of the other socio-economic indicators. We found no evidence for causal effects of income or occupation on self-longevity. Mediation analyses conducted in predominantly European-descent individuals through two-step Mendelian randomization suggested that among 59 candidates, cigarettes per day, body mass index, waist-to-hip ratio, hypertension, coronary heart disease, myocardial infarction, stroke, Alzheimer's disease, type 2 diabetes, heart failure and lung cancer individually played substantial mediating roles (proportion mediated, >10%) in the effect of education on specific longevity outcomes. These findings inform interventions for remediating longevity disparities attributable to socio-economic inequality.

Genetic Evidence for Causal Effects of Socioeconomic, Lifestyle, and Cardiometabolic Factors on Epigenetic-Age Acceleration.

GrimAge acceleration (GrimAgeAccel) and PhenoAge acceleration (PhenoAgeAccel) are DNA methylation-based markers of accelerated biological aging, standing out in predicting mortality and age-related cardiometabolic morbidities. Causal risk factors for GrimAgeAccel and PhenoAgeAccel are unclear. In this study, we performed 2-sample univariable and multivariable Mendelian randomization (MR) to investigate causal associations of 19 modifiable socioeconomic, lifestyle, and cardiometabolic factors with GrimAgeAccel and PhenoAgeAccel. Instrument variants representing 19 modifiable factors were extracted from genome-wide association studies (GWASs) with up to 1 million Europeans. Summary statistics for GrimAgeAccel and PhenoAgeAccel were derived from a GWAS of 34 710 Europeans. We identified 12 and 8 factors causally associated with GrimAgeAccel and PhenoAgeAccel, respectively. Smoking was the strongest risk factor (ß [standard error {SE}]: 1.299 [0.107] year) for GrimAgeAccel, followed by higher alcohol intake, higher waist circumference, daytime napping, higher body fat percentage, higher body mass index, higher C-reactive protein, higher triglycerides, childhood obesity, and type 2 diabetes; whereas education was the strongest protective factor (ß [SE]: -1.143 [0.121] year), followed by household income. Furthermore, higher waist circumference (ß [SE]: 0.850 [0.269] year) and education (ß [SE]: -0.718 [0.151] year) were the leading causal risk and protective factors for PhenoAgeAccel, respectively. Sensitivity analyses strengthened the robustness of these causal associations. Multivariable MR analyses further demonstrated independent effects of the strongest risk and protective factors on GrimAgeAccel and PhenoAgeAccel, respectively. In conclusion, our findings provide novel quantitative evidence on modifiable causal risk factors for accelerated epigenetic aging, suggesting promising intervention targets against age-related morbidity and improving healthy longevity.

Genetic susceptibility, family history of diabetes and healthy lifestyle factors in relation to diabetes: A gene-environment interaction analysis in Chinese adults.

AIMS/INTRODUCTION: To analyze the associations and interactions of the genetic susceptibility and family history of diabetes with lifestyle factors in relation to diabetes among Chinese adults. MATERIALS AND METHODS: We constructed a genetic risk score of 34 single-nucleotide polymorphisms in 11,596 participants from Songnan and Youyi communities, Baoshan District, Shanghai, China. We determined a healthy lifestyle by a normal body mass index (<24 kg/m2 ), adequate fruit and vegetable intake (≥4.5 cups/day), never smoked or quit smoking >1 year prior, sufficient physical activity (≥600 metabolic equivalent minutes per week), and a sleep duration of ≥6 to ≤8 h/day. Logistic regression models were used to examine the associations and interactions between heritability and lifestyle on diabetes. RESULTS: A healthier lifestyle was associated with a lower prevalence of diabetes within any heritable risk groups categorized by the genetic risk score and family history of diabetes. In the combined communities, the odds ratio (95% confidence interval) for diabetes associated with each additional healthy lifestyle factor was 0.83 (0.77-0.89) among participants with a low genetic risk score and 0.86 (0.81-0.91) among participants with a high genetic risk score (Pinteraction = 0.66). Similar interaction patterns of family history (Pinteraction = 0.15) and the combination of family history and the genetic risk score with healthy lifestyle (Pinteraction = 0.55) on diabetes were observed. CONCLUSIONS: A healthier lifestyle was associated with a significantly lower prevalence of diabetes regardless of heritable risk groups, highlighting the importance of adhering to a healthy lifestyle for diabetes prevention among the entire population.