Faculty, Staff and Student Publications

Language

English

Publication Date

5-30-2023

Journal

Nature Communications

DOI

10.1038/s41467-023-38800-2

PMID

37253714

PMCID

PMC10229598

PubMedCentral® Posted Date

5-30-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

Keywords

Humans, Quantitative Trait Loci, Ethnicity, Metabolome, Genome-Wide Association Study, Polymorphism, Single Nucleotide

Comments

This article has been corrected. See Nat Commun. 2023 Oct 19;14:6611.

Published Open-Access

no

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41467_2023_Article_42472.pdf (350 kB)
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