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

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.

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels

“…Proton NMR spectroscopy was used to measure amino acid levels. NMR methods have been described in detail previously [5]. Total circulating BCAA levels were defined as the sum of fasting isoleucine, leucine and valine levels.…”

“…Instrumental variables To generate an instrumental variable for circulating BCAA levels, we used publicly available GWAS meta-analysis results for isoleucine, leucine and valine levels from up to 24,900 individuals [5]. We calculated an unweighted GRS using the most significant variant associated with circulating BCAA levels in three of the four known BCAA loci (ESM Table 2).…”

“…Similarly, we tested for the association of fasting insulin GRS with valine, leucine, and isoleucine levels using GWAS summary results by Kettunen et al [5]. We implemented a multi-SNP genotype risk score method (R package 'gtx') used previously by Dastani et al [17].…”

“…Genetic variants identified in genome-wide association studies (GWAS) for circulating BCAA levels and insulin resistance can be utilised as instrumental variables in Mendelian randomisation [4][5][6], to examine causal relations between the two. So far, four variants have been shown to associate with circulating BCAA levels in the fasting state [5].…”

“…So far, four variants have been shown to associate with circulating BCAA levels in the fasting state [5]. The rs9637599 variant associated with circulating BCAA levels is located 2 kb upstream of the PPM1K gene, which encodes a mitochondrial phosphatase known to play a vital role in BCAA metabolism [7].…”