Circulating metabolite levels are highly heritable, and may reflect the state of the human organism in health and disease. Numerous autosomal loci associated with metabolite levels have been reported, predominantly in individuals of European ancestry. The genetic architecture of metabolites is not fully understood, including the generalizability of previous findings in European ancestry to other ancestries, and the genetic contribution of sex chromosomes.

We performed a whole-genome sequencing association (WGS) analysis of ~64 million common SNPs (minor allele frequency ≥ 1%) in up to 11,840 participants (5,940 European-Americans, 1,843 African-Americans and 4,059 Hispanic/Latino participants) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program and the NHGRI Centers for Common Disease Genomics (CCDG) with up to 1,666 circulating metabolites, quantified by liquid chromatography-mass spectrometry.

We discovered 2,741 novel variant-metabolite associations (spanning 257 genetic loci, including 93 novel), and validated 690 locus-metabolite associations reported previously (P < 3.0x10-11). The novel loci explained 1% - 28% of metabolite variation, and 27 associations were replicated in TwinsUK. Among the novel loci, ~27% contained genes involved in metabolism, and these loci were enriched in genes that cause inborn errors of metabolism (P = 2.3x10-10). We further demonstrated that the X chromosome was extensively involved in the metabolite regulation. Two missense variants located in ASMTL, encoding a protein implicated in cell division arrest, were associated with lower levels of three aromatic compounds (O-methylcatechol sulfate, tryptophan and 8-methoxykynurenate). Mendelian Randomization analysis revealed that several metabolites had levels increased based upon genotype that were associated with a 7%-14% risk change of coronary artery disease. These metabolites included succinoyltaurine, a derivative of taurine, which has long been suspected to be protective of atherosclerosis.

In summary, we conducted the first multi-ethnic WGS study of genetic determinants of circulating metabolites, and identified novel genetic loci, involved in miscellaneous biological processes, contributing to our understanding of human disease.