Genetic and lifestyle risks of cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Over the past 5 decades, the identification and modification of cardiovascular risk factors, as well as the development of pharmaceutical and interventional therapies, have resulted in declining CVD mortality rates. To develop better and innovative preventive strategies, a better understanding of the pathophysiological mechanisms underlying CVD is necessary. Studying the genetic factors underlying CVD and their risk factors may aid us in this undertaking.Genome-wide association studies have identified thousands of associations between genetic variants with risk factors and diseases, thereby increasing our understanding of the biology underlying these traits. The evidence for a causal relationship between a risk factor and a disease can then be investigated using these genetic variants.This thesis presents evidence for causal relationships between risk factors such as telomere length and iron parameters, with CVD. We uncovered novel genetic variants associated with lipoprotein(a), but also with lifestyle factors such as caffeine intake and sedentary behaviors. We subsequently provide evidence for their causal relations with coronary artery disease. Additionally, we found genetic and lifestyle factors had additive effects on the risk of developing CVD. A healthy lifestyle was associated with lower risks compared to an unhealthy lifestyle, regardless of the genetic risk, and a high genetic risk with an unhealthy lifestyle both increased the risk of developing CVD. The findings described in this thesis help us better understand the pathophysiological mechanisms underlying CVD and may aid in improving risk stratifications

Genome-wide association studies and Mendelian randomization analyses for leisure sedentary behaviours

Leisure sedentary behaviours are associated with increased risk of cardiovascular disease, but whether this relationship is causal is unknown. The aim of this study is to identify genetic determinants associated with leisure sedentary behaviours and to estimate the potential causal effect on coronary artery disease (CAD). Genome wide association analyses of leisure television watching, leisure computer use and driving behaviour in the UK Biobank identify 145, 36 and 4 genetic loci (P < 1×10−8), respectively. High genetic correlations are observed between sedentary behaviours and neurological traits, including education and body mass index (BMI). Two-sample Mendelian randomization (MR) analysis estimates a causal effect between 1.5 hour increase in television watching and CAD (OR 1.44, 95%CI 1.25–1.66, P = 5.63 × 10−07), that is partially independent of education and BMI in multivariable MR analyses. This study finds independent observational and genetic support for the hypothesis that increased sedentary behaviour by leisure television watching is a risk factor for CAD

Is genetic liability to ADHD and ASD causally linked to educational attainment?

Background The association patterns of Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) with educational attainment (EA) are complex; children with ADHD and ASD are at risk of poor academic outcomes, and parental EA has been associated with risk of ADHD/ASD in the offspring. Little is known on the causal links between ADHD, ASD, EA and the potential contribution of cognitive ability. Methods Using the latest genome-wide association studies (GWAS) summary data on ADHD, ASD and EA, we applied two-sample Mendelian randomization (MR) to assess the effects of genetic liability to ADHD and ASD on EA. Reverse direction analyses were additionally performed. Multivariable MR was performed to estimate any effects independent of cognitive ability. Results Genetic liability to ADHD had a negative effect on EA, independently of cognitive ability (MVMRIVW: -1.7 months of education per doubling of genetic liability to ADHD; 95% CI: -2.8 to -0.7), whereas genetic liability to ASD a positive effect (MVMRIVW: 30 days per doubling of the genetic liability to ASD; 95% CI: 2 to 53). Reverse direction analyses suggested that genetic liability to higher EA had an effect on lower risk of ADHD, independently of cognitive ability (MVMRIVWOR: 0.33 per SD increase; 95% CI: 0.26 to 0.43) and increased risk of ASD (MRIVWOR: 1.51 per SD increase; 95% CI: 1.29 to 1.77), which was partly explained by cognitive ability (MVMRIVWOR per SD increase: 1.24; 95%CI: 0.96 to 1.60). Conclusions Genetic liability to ADHD and ASD is likely to affect educational attainment, independently of underlying cognitive ability

Optimizing Exposome-wide Assessments in Cardiometabolic Risk

This thesis is focused on cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D), two concomitant conditions that appear with growing concern. In our work, we aim to improve the identification of individuals at-risk of cardiometabolic disease through the characterization of complex environmental exposures (i.e. diet, physical activity), that temporally vary, and the health effects on cardiometabolic traits and disease. Our projects were based upon the Västerbotten Health Survey (VHU) and the Malmö Diet and Cancer (MDCS) studies, which included extensive data on lifestyle, biological intermediates, and clinical outcomes. In Paper I, we utilized the so-called environmental-wide association approach (EWAS), using longitudinal data from > 31,000 adults in VHU study. Under generalized linear models, from ~ 300 candidate exposures, 11 modifiable variables were associated with most of the cardiometabolic traits; the prioritised variables belonged to smoking, coffee intake, physical activity, alcohol intake, and context-specific lifestyle domains. In Paper II, we implemented a machine learning-based model to identify individuals with variable susceptibility to lifestyle risk factors for T2D and CVD. Individuals with sensitivity to blood lipids, and blood pressure associated predictors were at higher risk to develop cardiometabolic disease. Furthermore, when pooling across sensitive groups from the two cohorts, the findings suggest a particular vulnerable subpopulation with different risk profile. In Paper III, a series of causal-inference experiments from VHU and publicly available genome-wide association study (GWAS) summary statistics were used to triangulate evidence of the direct and mediated effects by adiposity and physical activity, of macronutrient intake (fat, carbohydrates, protein and sugar) and cardiometabolic disease. Using structural equation modelling, the mediation analyses enhanced with Mendelian randomization analysis, showed a likely causal putative association between carbohydrate intake and T2D. In addition, the integrative genomic analyses suggested a candidate causal variant localized to the established T2D gene TCF7L2. In Paper IV, we conducted a systematic review and metanalysis of observational studies, complemented by Mendelian randomization analysis using GWAS summary statistics, investigating causal associations of individuals with high, yet normal, glycaemia associated with cardiovascular complications. Prediabetes was likely causally associated with coronary heart disease; suggesting higher, but not diabetic levels of blood glucose confer a risk, thus, effective preventive strategies may prove successful in prediabetes

The impact of education inequality on rheumatoid arthritis risk is mediated by smoking and body mass index: mendelian randomization study

Objective To estimate the causal relationship between educational attainment—as a proxy for socioeconomic inequality—and risk of RA, and quantify the roles of smoking and BMI as potential mediators. Methods Using the largest genome-wide association studies (GWAS), we performed a two‐sample Mendelian randomization (MR) study of genetically predicted educational attainment (instrumented using 1265 variants from 766 345 individuals) and RA (14 361 cases, 43 923 controls). We used two-step MR to quantify the proportion of education’s effect on RA mediated by smoking exposure (as a composite index capturing duration, heaviness and cessation, using 124 variants from 462 690 individuals) and BMI (517 variants, 681 275 individuals), and multivariable MR to estimate proportion mediated by both factors combined. Results Each S.D. increase in educational attainment (4.2 years of schooling) was protective of RA (odds ratio 0.37; 95% CI: 0.31, 0.44). Higher educational attainment was also protective for smoking exposure (β = −0.25 S.D.; 95% CI: −0.26, −0.23) and BMI [β = −0.27 S.D. (∼1.3 kg/m2); 95% CI: −0.31, −0.24]. Smoking mediated 24% (95% CI: 13%, 35%) and BMI 17% (95% CI: 11%, 23%) of the total effect of education on RA. Combined, the two risk factors explained 47% (95% CI: 11%, 82%) of the total effect. Conclusion Higher educational attainment has a protective effect on RA risk. Interventions to reduce smoking and excess adiposity at a population level may reduce this risk, but a large proportion of education’s effect on RA remains unexplained. Further research into other risk factors that act as potentially modifiable mediators are required

Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses.

Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, heart failure, hemorrhagic stroke, lipid-lowering medication, and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (β systolic BP ≥2.63; β diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; P≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, P=0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D