Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites
- 6 March 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 49 (4), 568-578
- https://doi.org/10.1038/ng.3809
Abstract
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.Keywords
This publication has 61 references indexed in Scilit:
- Further Improvements to Linear Mixed Models for Genome-Wide Association StudiesScientific Reports, 2014
- Isaac: ultra-fast whole-genome secondary analysis on Illumina sequencing platformsBioinformatics, 2013
- Estimating heritability for cause specific mortality based on twin studiesLifetime Data Analysis, 2013
- A genome-wide association study of metabolic traits in human urineNature Genetics, 2011
- Genetics Meets Metabolomics: A Genome-Wide Association Study of Metabolite Profiles in Human SerumPLoS Genetics, 2008
- The SWISS-MODEL Repository and associated resourcesNucleic Acids Research, 2008
- Circulating 1,5-Anhydroglucitol Levels in Adult Patients With Diabetes Reflect Longitudinal Changes of GlycemiaDiabetes Care, 2004
- Structural and mutational characterization of l-carnitine binding to human carnitine acetyltransferaseJournal of Structural Biology, 2004
- KEGG: Kyoto Encyclopedia of Genes and GenomesNucleic Acids Research, 2000
- Sources and Physiological Significance of Plasma Dopamine SulfateJournal of Clinical Endocrinology & Metabolism, 1999