The influence of rare variants in circulating metabolic biomarkers

Autor: Nicole Soranzo, Eleftheria Zeggini, Emanuele Di Angelantonio, Interval Study, Kousik Kundu, Adam S. Butterworth, Fernando Riveros-Mckay, Willem H. Ouwehand, Clare Oliver-Williams, Klaudia Walter, Inês Barroso, Eleanor Wheeler, John Danesh, Savita Karthikeyan, David J. Roberts
Přispěvatelé: Riveros-Mckay, Fernando [0000-0002-6671-1177], Oliver-Williams, Clare [0000-0002-3573-2426], Karthikeyan, Savita [0000-0002-4798-5746], Walter, Klaudia [0000-0003-4448-0301], Kundu, Kousik [0000-0002-1019-8351], Ouwehand, Willem H [0000-0002-7744-1790], Wheeler, Eleanor [0000-0002-8616-6444], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Ouwehand, Willem H. [0000-0002-7744-1790]
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
Cancer Research
Apolipoprotein B
Metabolite
Genome-wide association study
Disease
QH426-470
Biochemistry
chemistry.chemical_compound
0302 clinical medicine
Mathematical and Statistical Techniques
Drug Metabolism
Medicine and Health Sciences
Genetics (clinical)
0303 health sciences
Statistics
Genomics
Metaanalysis
Pyruvate dehydrogenase complex
Phenotype
Lipids
3. Good health
Cholesterol
Cardiovascular Diseases
Physical Sciences
Lipoprotein disorder
Female
lipids (amino acids
peptides
and proteins)
Research Article
medicine.medical_specialty
Lipoproteins
Computational biology
Biology
Research and Analysis Methods
03 medical and health sciences
Internal medicine
medicine
Genome-Wide Association Studies
Genetics
Humans
Pharmacokinetics
Statistical Methods
Molecular Biology
Gene
Ecology
Evolution
Behavior and Systematics
Triglycerides
030304 developmental biology
Pharmacology
Genetic Variation
Biology and Life Sciences
Computational Biology
Proteins
Human Genetics
Metabolism
Cholesterol
LDL
Genome Analysis
Lipid Metabolism
Endocrinology
chemistry
biology.protein
Drug metabolism
030217 neurology & neurosurgery
Biomarkers
Mathematics
Lipoprotein
Genome-Wide Association Study
Zdroj: PLoS Genetics, Vol 16, Iss 3, p e1008605 (2020)
PLoS Genetics
PLoS Genet. 16:e1008605 (2020)
ISSN: 1553-7404
1553-7390
Popis: 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
Author summary Cardiovascular diseases (CVD) are the number one cause of death globally. Various metabolic biomarkers including lipid and lipoprotein particles have been implicated as risk factors for the development of CVD. Understanding how these biomarkers are regulated can lead to increased understanding of CVD aetiology and the potential identification of drug targets. Here we take advantage of high resolution measurements on a large cohort of 7,142 healthy blood donors with whole-exome and whole-genome sequencing data to explore the influence of rare variation on circulating metabolic biomarker levels. Using a novel approach leveraging the information gained from various measurements on the same participants we are able to identify a novel biological pathway involved in the regulation of intermediate-density and low-density lipoproteins as well as circulating cholesterol, confirm various established gene associations and identify potential novel gene associations that merit further replication. This work highlights the advantages that can be gained by combining high resolution genotypic and phenotypic measurements in one large cohort.
Databáze: OpenAIRE
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