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The influence of rare variants in circulating metabolic biomarkers

Published version
Peer-reviewed

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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 large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.

Description

Keywords

Research Article, Biology and life sciences, Medicine and health sciences, Research and analysis methods, Physical sciences

Journal Title

PLOS Genetics

Conference Name

Journal ISSN

1553-7390
1553-7404

Volume Title

16

Publisher

Public Library of Science
Sponsorship
National Institute for Health Research (NIHR bioresource, NIHR Cambridge Biomedical Research Centre)
Seventh Framework Programme (HEALTH-F2-2012-279233)
National Institute for Health Research (NIHR BTRU-2014-10024)
Medical Research Council (MR/L003120/1)
British Heart Foundation (RG/13/13/30194)
Wellcome Trust (WT206194)
Consejo Nacional de Ciencia y Tecnología (RE/13/6/30180))