Association of genetically predicted levels of circulating blood lipids with coronary artery disease incidence.

Background And Aims: Estimating the genetic risk of coronary artery disease (CAD) is now possible by aggregating data from genome-wide association studies (GWAS) into polygenic risk scores (PRS). Combining multiple PRS for specific circulating blood lipids could improve risk prediction. Here, we sought to evaluate the performance of PRS derived from CAD and blood lipids GWAS to predict the incidence of CAD.

Impact of loss-of-function in angiopoietin-like 4 on the human phenome.

Background: Carriers of the E40K loss-of-function variant in Angiopoietin-like 4 (ANGPTL4), have lower plasma triglyceride levels as well as lower rates of coronary artery disease (CAD) and type 2 diabetes (T2D). These genetic data suggest ANGPTL4 inhibition as a potential therapeutic target for cardiometabolic diseases. However, it is unknown whether the association between E40K and human diseases is due to linkage disequilibrium confounding.

Large-scale metabolomic profiling and incident non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent disease with no specific drug therapy. High-throughput metabolomics present an unprecedented opportunity to identify biomarkers and potentially causal risk factors for NAFLD. Here, we determined the impact of 21 circulating metabolites, 17 lipids, and 132 lipoprotein particle characteristics on NAFLD combining prospective observational and two-sample Mendelian randomization (MR) analyses in 121,032 UK Biobank participants.

Genetic control of body weight by the human brain proteome.

Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with body weight but the biological relevance of most remains unexplored. Given the critical role of the brain in body weight regulation, we set out to determine whether genetic variants linked with body mass index (BMI) could be mapped to brain proteins. Using genetic colocalization, we mapped 25 loci from the largest BMI GWAS (n = 806,834) to brain protein concentrations obtained from publicly available datasets.

Proteome-Wide Mendelian Randomization Identifies Causal Links Between Blood Proteins and Acute Pancreatitis.

Background & Aims: Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP.

Mendelian randomization prioritizes abdominal adiposity as an independent causal factor for liver fat accumulation and cardiometabolic diseases.

Background: Observational studies have linked adiposity and especially abdominal adiposity to liver fat accumulation and non-alcoholic fatty liver disease. These traits are also associated with type 2 diabetes and coronary artery disease but the causal factor(s) underlying these associations remain unexplored.

Methods: We used a multivariable Mendelian randomization study design to determine whether body mass index and waist circumference were causally associated with non-alcoholic fatty liver disease using publicly available genome-wide association study summary statistics of the UK Biobank ( = 461,460) and of non-alcoholic fatty liver disease (8434 cases and 770,180 control).

Mendelian Randomization Analysis Identifies Blood Tyrosine Levels as a Biomarker of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease associated with premature mortality. Its diagnosis is challenging, and the identification of biomarkers causally influenced by NAFLD may be clinically useful. We aimed at identifying blood metabolites causally impacted by NAFLD using two-sample Mendelian randomization (MR) with validation in a population-based biobank.

Blood Levels of the Hepatokine Are Not Causally Linked with Type 2 Diabetes: A Bidirectional Mendelian Randomization Study.

Hepatokines are liver-derived proteins that may influence metabolic pathways such as insulin sensitivity. Recently, Sparc-related modular calcium-binding protein 1 (SMOC1) was identified as glucose-responsive hepatokine that is dysregulated in the setting of non-alcoholic fatty liver disease (NAFLD). While may influence glucose-insulin homeostasis in rodents, it is unknown if is influenced by NAFLD in humans.

Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked to several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluating their functional consequences. We performed a genome-wide meta-analysis of 4 cohorts of electronic health record-documented NAFLD in participants of European ancestry (8,434 cases and 770,180 controls).

Circulating Galectin-3 Levels Are Not Associated With Nonalcoholic Fatty Liver Disease: A Mendelian Randomization Study.

Context: The impact of galectin-3 inhibitors on nonalcoholic fatty liver diseases (NAFLD)-related outcomes is currently under investigation in randomized clinical trials. Whether there is a causal association between plasma galectin-3 levels and NAFLD is unknown.

Objective: To evaluate the causal effect of circulating galectin-3 levels on NAFLD as well as >800 other human diseases.