Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

TLDR

Genome‑wide association studies have uncovered many loci linked to complex diseases, yet the underlying molecular mechanisms remain largely unknown, and metabolite profiling offers a heritable trait platform to illuminate disease pathophysiology. This study extends a genome‑wide association analysis of 123 circulating metabolites measured by nuclear magnetic resonance in up to 24,925 individuals to identify novel genetic loci. The authors performed a large‑scale GWAS of NMR‑derived metabolites, followed by genetic fine‑mapping and Mendelian randomization to reveal causal effects of lipoprotein(a) on lipoprotein metabolism and to evaluate pleiotropic impacts on multiple morbidities using electronic health‑record data. They identified eight new loci for amino acids, pyruvate, and fatty acids, demonstrated that the LPA locus associates with cardiovascular risk through extensive links to very‑low‑density lipoprotein and triglyceride metabolism, and provided evidence that targeting LPA could safely reduce cardiovascular risk.

Abstract

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.