Year: 2020
Type: review
Study design: Observational Study
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.
Source: PLoS Genetics
Institutions: Wellcome Sanger Institute, University of Cambridge, NHS Blood and Transplant, John Radcliffe Hospital, National Institute for Health and Care Research, University of Oxford, Health Data Research UK, NIHR Cambridge Biomedical Research Centre, Wellcome/MRC Institute of Metabolic Science, Addenbrooke's Hospital, MRC Epidemiology Unit, Wellcome Trust, Helmholtz Munich
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: NHS Blood and Transplant, Wellcome Trust, Scottish Government, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, University of Cambridge, European Commission, Public Health Agency, Cambridge University Hospitals, Consejo Nacional de Ciencia y Tecnología, Chief Scientist Office, Scottish Government Health and Social Care Directorate, NIHR BioResource, Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Seventh Framework Programme, Homerton College, University of Cambridge, Health and Social Care Research and Development Division, NIHR Cambridge Biomedical Research Centre, Health Data Research UK
Awards: Aetiology of type 2 diabetes and related metabolic disorders, G1727433039, G1953244154, Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal), G2797452859, G2804450655, G3217060148, G3425072377, G3783408021, G3986547339, G4194769985, G4584873075, G4642712072, G5003223212, G5117680084, G587296758, G6467398148, EPIC-CVD: Individualised CVD risk assessment: tailoring targeted and cost-effective approaches to Europe's diverse populations, G6550979745, G6787924332, Wellcome Trust Sanger Institute - generic account for deposition of all core- funded research papers., Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application (renewal). (Joint funding with MRC), G7939076303, G7992221752, Research Excellence, G8346449347, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application
OpenAlex ID: W3009409673