PLoS Genetics (Mar 2020)

The influence of rare variants in circulating metabolic biomarkers.

  • Fernando Riveros-Mckay,
  • Clare Oliver-Williams,
  • Savita Karthikeyan,
  • Klaudia Walter,
  • Kousik Kundu,
  • Willem H Ouwehand,
  • David Roberts,
  • Emanuele Di Angelantonio,
  • Nicole Soranzo,
  • John Danesh,
  • INTERVAL Study,
  • Eleanor Wheeler,
  • Eleftheria Zeggini,
  • Adam S Butterworth,
  • Inês Barroso

DOI
https://doi.org/10.1371/journal.pgen.1008605
Journal volume & issue
Vol. 16, no. 3
p. e1008605

Abstract

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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.