Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA
نویسندگان
چکیده
Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.
منابع مشابه
Unveiling the genetic loci for a panicle developmental trait using genome-wide association study in rice
Panicle size has a high correlation with grain yield in rice. There is a bottleneck to identify the additional quantitative trait loci (QTL) for panicle size due to the conventional traits used for QTL mapping. To identify more genetic loci for panicle size, a panicle developmental trait (LNTB, the length from panicle neck-knot to the first primary branch in the rachis) related to panicle size ...
متن کاملGenome-wide association study evaluating lipoprotein-associated phospholipase A2 mass and activity at baseline and after rosuvastatin therapy.
BACKGROUND Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a proinflammatory enzyme bound to low-density lipoprotein cholesterol and other circulating lipoproteins. Two measures of Lp-PLA(2), mass and activity, are associated with increased cardiovascular risk. Data are sparse regarding genetic determinants of Lp-PLA(2) mass and activity, and no prior data are available addressing gene...
متن کاملA genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.
Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 mid...
متن کاملNovel genetic associations with serum level metabolites identified by phenotype set enrichment analyses.
Availability of standardized metabolite panels and genome-wide single-nucleotide polymorphism data endorse the comprehensive analysis of gene-metabolite association. Currently, many studies use genome-wide association analysis to investigate the genetic effects on single metabolites (mGWAS) separately. Such studies have identified several loci that are associated not only with one but with mult...
متن کاملGenome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease
Metabolites derived from dietary choline and L-carnitine, such as trimethylamine N-oxide and betaine, have recently been identified as novel risk factors for atherosclerosis in mice and humans. We sought to identify genetic factors associated with plasma betaine levels and determine their effect on risk of coronary artery disease (CAD). A two-stage genome-wide association study (GWAS) identifie...
متن کامل