Abstract
Metabolites are small products of metabolism that provide a snapshot of the wellbeing of an organism and the mechanisms that control key physiological processes involved in health and disease. Here we report the results of a genome-wide association study of 722 circulating metabolite levels in 8809 subjects of European origin, providing both breadth and depth. These analyses identified 202 unique genomic regions whose variations are associated with the circulating levels of 478 different metabolites. Replication with a subset of 208 metabolites that were available in an independent dataset for a cohort of 1768 European subjects confirmed the robust associations, including 74 novel genomic regions not associated with any metabolites in previous works. This study enhances our knowledge of genetic mechanisms controlling human metabolism. Our findings have major potential for identifying novel targets and developing new therapeutic strategies.
Highlights
Metabolism denotes the repertoire of biochemical processes that sustain the life of a cell or organism
Various factors impede our understanding of the genetic control mechanisms of the human metabolome, including insufficient resolution for the characterization of both genetic and metabolite markers, and the statistical power limitations of most available cohorts
We report a genome-wide association study (GWAS) of 722 circulating blood metabolite levels using over 10 million Haplotype Reference Consortium-imputed genetic markers from up to 8809 European participants of the NIHR UK Bioresource cohort
Summary
Metabolism denotes the repertoire of biochemical processes that sustain the life of a cell or organism. We report a genome-wide association study (GWAS) of 722 circulating blood metabolite levels using over 10 million Haplotype Reference Consortium-imputed genetic markers from up to 8809 European participants of the NIHR UK Bioresource cohort. Genetic variants associated with metabolites in our analyses displayed significant eQTL effects in different tissues (Table S5), often in several genes. The directions of the genetic effects were remarkably consistent in both datasets, for all the other SNPs that were significantly associated with metabolites in the discovery cohort (Figure 2) The metaanalysis of these 201 metabolites identified two additional unique genomic regions for which we report new associations with metabolite levels (Table S8), bringing the total of newly associated metabolically active loci to 74. More work will be needed in the future to identify variants of functional relevance amid clusters of genetic variants in linkage disequilibrium with each other, and to clarify the roles of the particular genes and transcripts in the control of metabolic processes
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