TY - JOUR
T1 - The influence of rare variants in circulating metabolic biomarkers
AU - INTERVAL Study
AU - Riveros-Mckay, Fernando
AU - Oliver-Williams, Clare
AU - Karthikeyan, Savita
AU - Walter, Klaudia
AU - Kundu, Kousik
AU - Ouwehand, Willem H.
AU - Roberts, David
AU - Angelantonio, Emanuele Di
AU - Soranzo, Nicole
AU - Danesh, John
AU - Wheeler, Eleanor
AU - Zeggini, Eleftheria
AU - Butterworth, Adam S.
AU - Barroso, Inês
N1 - Publisher Copyright:
© 2020 Riveros-Mckay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85082780224&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1008605
DO - 10.1371/journal.pgen.1008605
M3 - Article
C2 - 32150548
AN - SCOPUS:85082780224
SN - 1553-7390
VL - 16
JO - PLoS Genetics
JF - PLoS Genetics
IS - 3
M1 - e1008605
ER -
