The influence of rare variants in circulating metabolic biomarkers.

PLoS Genetics
Fernando Riveros-MckayInês Barroso

Abstract

Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT<2.41x10-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As lar...Continue Reading

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Citations

Nov 4, 2020·Journal of Nuclear Cardiology : Official Publication of the American Society of Nuclear Cardiology·G AngelidisP Georgoulias

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Methods Mentioned

BETA
nuclear magnetic resonance
NMR
PCA

Software Mentioned

ORPHANET
CAP
METASKAT
R
O R package
INTERVAL
Reactome
ANNOVAR
DisGeNET
BWA

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