Feofanova, Elena V.Brown, Michael R.Alkis, TarynManuel, Astrid M.Li, XihaoTahir, Usman A.Li, ZilinMendez, Kevin M.Kelly, Rachel S.Qi, QibinChen, HanLarson, Martin G.Lemaitre, Rozenn N.Morrison, Alanna C.Grieser, CharlesWong, Kari E.Gerszten, Robert E.Zhao, ZhongmingLasky-Su, JessicaNHLBI Trans-Omics for Precision Medicine (TOPMed)Yu, Bing2024-01-252024-01-252023-05-30Feofanova EV, Brown MR, Alkis T, et al. Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations [published correction appears in Nat Commun. 2023 Oct 19;14(1):6611]. Nat Commun. 2023;14(1):3111. Published 2023 May 30. doi:10.1038/s41467-023-38800-2https://hdl.handle.net/1805/38187Circulating 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.en-USAttribution 4.0 InternationalGenome-wide association studiesMetabolomicsPredictive markersArticle