Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations

Elena V. Feofanova, Michael R. Brown, Taryn Alkis, Astrid M. Manuel, Xihao Li, Usman A. Tahir, Zilin Li, Kevin M. Mendez, Rachel S. Kelly, Qibin Qi, Han Chen, Martin G. Larson, Rozenn N. Lemaitre, Alanna C. Morrison, Charles Grieser, Kari E. Wong, Robert E. Gerszten, Zhongming Zhao, Jessica Lasky-Su and Bing Yu ()
Additional contact information
Elena V. Feofanova: The University of Texas Health Science Center
Michael R. Brown: The University of Texas Health Science Center
Taryn Alkis: The University of Texas Health Science Center
Astrid M. Manuel: The University of Texas Health Science Center at Houston
Xihao Li: Harvard T.H. Chan School of Public Health
Usman A. Tahir: Harvard Medical School
Zilin Li: Harvard T.H. Chan School of Public Health
Kevin M. Mendez: Brigham and Women’s Hospital and Harvard Medical School
Rachel S. Kelly: Brigham and Women’s Hospital and Harvard Medical School
Qibin Qi: Albert Einstein College of Medicine
Han Chen: The University of Texas Health Science Center
Martin G. Larson: Boston University School of Public Health
Rozenn N. Lemaitre: University of Washington
Alanna C. Morrison: The University of Texas Health Science Center
Charles Grieser: Metabolon Inc.
Kari E. Wong: Metabolon Inc.
Robert E. Gerszten: Fred Hutchinson Cancer Research Center
Zhongming Zhao: The University of Texas Health Science Center
Jessica Lasky-Su: Brigham and Women’s Hospital and Harvard Medical School
Bing Yu: The University of Texas Health Science Center

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38800-2

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