Combining Genomics and Metabolomics — WGS identifies common-to-rare variants associated with human blood metabolites

First was the study of “the genome” and they called it “genomics.” Then came the sequencing of the coding regions (exons) from mRNA transcribed from the DNA, and they called it “transcriptomics.” Then came the protein sequences, called of course “proteomics.” And finally, looking at the metabolites by chromatography systems combined with tandem mass spectrometry, they started looking at “metabolomics.” Next, questions began arising as to how to correlate DNA sequence changes with alterations in metabolite profiles.

The attached paper describes genetic factors modifying the blood metabolome –– that have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. Authors conducted a whole-genome sequencing (WGS) study of common, low-frequency and rare variants, and searched for associations of genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults.

Authors analyzed 644 metabolites with consistent levels across three longitudinal-data collections. Genetic sequence variations at 101 genetic loci were associated with the levels of 246 (38%) metabolites (P ≤ 1.9 × 10–11). They identified 113 (10.7%), from among 1,054 unrelated individuals in the cohort, who carried heterozygous rare variants that are likely influencing the function of 17 genes. Thirteen of the 17 genes are associated with inborn-errors-of-metabolism or other pediatric genetic conditions. These data extend the map of loci influencing the metabolome and highlight the importance of heterozygous rare variants in determining abnormal blood metabolic phenotypes in adults.

Nature Genet    April 2o17; 49: 568–578

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