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Genome-wide characterization of circulating metabolic biomarkers.

Published version
Peer-reviewed

Repository DOI


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Authors

Karjalainen, Minna K  ORCID logo  https://orcid.org/0000-0003-3184-3775
Karthikeyan, Savita 
Oliver-Williams, Clare 

Abstract

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

Description

Acknowledgements: Please see the Supplementary Notes for acknowledgements and funding.

Keywords

Female, Humans, Pregnancy, Acetone, Biomarkers, Cholestasis, Intrahepatic, Cohort Studies, Genome-Wide Association Study, Hypertension, Lipoproteins, Magnetic Resonance Spectroscopy, Mendelian Randomization Analysis, Metabolic Networks and Pathways, Metabolomics, Phenotype, Polymorphism, Single Nucleotide, Pregnancy Complications

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

628

Publisher

Springer Science and Business Media LLC
Sponsorship
National Institute for Health Research (NIHR) (via Cambridge University Hospitals NHS Foundation Trust (CUH)) (Unknown)
Department of Health (via National Institute for Health Research (NIHR)) (NIHR203337)
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (RG/18/13/33946)