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

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.

Coupling of metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and resulting traits and diseases

“…Comparison of our results to those from published studies that focused on rare variant aggregation testing of metabolite levels [14][15][16][17][18][19][20]24 (Methods) showed that 32 of the 73 identified unique genes (44%) had not been reported as significant in any of these studies. Moreover, 115 of all 192 detected gene-metabolite associations (60%) were novel (Supplementary Table 4).…”

“…We compared our significant findings to the significant findings from eight published genetic studies of the plasma/serum or urine metabolome that focused on rare exonic variant aggregation testing and used sequencing and high-throughput metabolomics data [14][15][16][17][18][19][20]24 . We first assessed whether the genes identified in our study were reported as associated with any metabolite in any of the seven studies at their respective multiple-testing corrected significance threshold, after having mapped all gene names to their current version in Ensembl version 109 using https://www.ensembl.org/biomart/martview.…”

“…Gene-based aggregation testing of rare, putatively damaging variants in population studies can address this challenge. Previously, such studies have focused almost exclusively on the circulating metabolome [14][15][16][17][18][19][20] . We have recently shown that GWAS of paired plasma and urine metabolomes not only reveal many more associations, but also enable specific insights into renal metabolite handling 2 .…”

Advancing equity in human genomics through tissue-specific multi-ancestry molecular data

“…Recently, large initiatives that include genetic data from diverse populations, such as the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program, have included proteomics and metabolomics data from blood. 9 , 10 …”

Metabolites, Healthy Lifestyle, and Polygenic Risk Score Associated with Upper Gastrointestinal Cancer: Findings from the UK Biobank Study

“…In addition, genetic factors are strongly associated with the incidence of UGI cancer. − Polygenic risk score (PRS) is constructed by incorporating numerous single nucleotide polymorphisms (SNPs), thereby reflecting an individual’s genetic susceptibility to a particular condition. This facilitates the categorization of populations into different risk strata, enabling personalized health lifestyle interventions or early disease screening. , Several studies have demonstrated that levels of certain metabolites are associated with disease genotypic risk, indicating that metabolite levels have a high heritability. , …”