ABSTRACT
Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.
Subject(s)
Cholesterol/blood , Coronary Artery Disease/genetics , Genetic Loci , Lipid Metabolism/genetics , Phytosterols/blood , ABO Blood-Group System/blood , ABO Blood-Group System/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 5/blood , ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 8/blood , ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics , Adult , Apolipoproteins E/blood , Apolipoproteins E/genetics , Coronary Artery Disease/blood , Coronary Artery Disease/pathology , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Hydroxymethylglutaryl CoA Reductases/blood , Hydroxymethylglutaryl CoA Reductases/genetics , Lipase/blood , Lipase/genetics , Lipoproteins/blood , Lipoproteins/genetics , Male , Membrane Transport Proteins/blood , Membrane Transport Proteins/genetics , Mendelian Randomization Analysis , Multifactorial Inheritance , Polymorphism, Single Nucleotide , Scavenger Receptors, Class B/blood , Scavenger Receptors, Class B/geneticsABSTRACT
DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
