The influence of rare variants in circulating metabolic biomarkers
Autoři:
Fernando Riveros-Mckay aff001; Clare Oliver-Williams aff002; Savita Karthikeyan aff002; Klaudia Walter aff001; Kousik Kundu aff001; Willem H. Ouwehand aff001; David Roberts aff006; Emanuele Di Angelantonio aff001; Nicole Soranzo aff001; John Danesh aff001; Eleanor Wheeler aff001; Eleftheria Zeggini aff001; Adam S. Butterworth aff001; Inês Barroso aff001;
Působiště autorů:
Wellcome Sanger Institute, Cambridge, United Kingdom
aff001; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
aff002; Homerton College, Cambridge, United Kingdom
aff003; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
aff004; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom
aff005; The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
aff006; NHS Blood and Transplant—Oxford Centre, Level 2, John Radcliffe Hospital, Oxford, United Kingdom
aff007; Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
aff008; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom
aff009; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, United Kingdom
aff010; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom
aff011; MRC Epidemiology Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
aff012; Institute of Translational Genomics, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany
aff013
Vyšlo v časopise:
The influence of rare variants in circulating metabolic biomarkers. PLoS Genet 16(3): e32767. doi:10.1371/journal.pgen.1008605
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008605
Souhrn
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.
Klíčová slova:
Biomarkers – Drug metabolism – Genome-wide association studies – Cholesterol – Lipid metabolism – Lipids – Lipoproteins – Metaanalysis
Zdroje
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