Genetic factors modifying the blood metabolome have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. We conducted a whole-genome sequencing study of common, low-frequency and rare variants to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults. We focused the analysis on 644 metabolites with consistent levels across three longitudinal data collections. Genetic sequence variations at 101 loci were associated with the levels of 246 (38%) metabolites (P ≤ 1.9 × 10−11). We identified 113 (10.7%) among 1,054 unrelated individuals in the cohort who carried heterozygous rare variants likely influencing the function of 17 genes. Thirteen of the 17 genes are associated with inborn errors of metabolism or other pediatric genetic conditions. This study extends the map of loci influencing the metabolome and highlights the importance of heterozygous rare variants in determining abnormal blood metabolic phenotypes in adults.
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The sequencing and metabolome study was funded by Human Longevity, Inc. TwinsUK was funded by the Wellcome Trust, European Community's Seventh Framework Programme (FP7/2007-2013 277849, 201413 and 259749). The study also receives support from the National Institute for Health Research (NIHR) Clinical Research Facility at Guy's and St Thomas' NHS Foundation Trust and the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. T.D.S. is an NIHR senior Investigator.
The following authors are current employees or stockholders of Human Longevity, Inc.: J.C.V., A.T., T.L., M.H., H.-C.Y., W.H.B., E.F.K., S.B., Y.T., B.A.P. and N.J.S. The following authors are current employees or stockholders of Metabolome, Inc.: A.M.E., L.A.D.M. and L.G.
Supplementary Figures 1–16 (PDF 7521 kb)
Metabolite h2 and outliers. (XLSX 166 kb)
GWAS significant independent variants. (XLSX 100 kb)
GWAS summary statistics. (XLSX 19696 kb)
GWAS comparison. (XLSX 104 kb)
SKAT results. (XLSX 155 kb)
Additional coding rare variants. (XLSX 32 kb)
Promoter rare variants in outliers. (XLSX 28 kb)
Rare variants from publications. (XLSX 30 kb)
Rare variants in genes from publications. (XLSX 30 kb)
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Long, T., Hicks, M., Yu, HC. et al. Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites. Nat Genet 49, 568–578 (2017). https://doi.org/10.1038/ng.3809
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