title: Genetics of the human metabolome, what is next?
abstract: Increases in throughput and decreases in costs have facilitated large scale metabolomics studies, the simultaneous measurement of large numbers of biochemical components in biological samples. Initial large scale studies focused on biomarker discovery for disease or disease progression and helped to understand biochemical pathways underlying disease. The first population-based studies that combined metabolomics and genome wide association studies (mGWAS) have increased our understanding of the (genetic) regulation of biochemical conversions. Measurements of metabolites as intermediate phenotypes are a potentially very powerful approach to uncover how genetic variation affects disease susceptibility and progression. However, we still face many hurdles in the interpretation of mGWAS data. Due to the composite nature of many metabolites, single enzymes may affect the levels of multiple metabolites and, conversely, levels of single metabolites may be affected by multiple enzymes. Here, we will provide a global review of the current status of mGWAS. We will specifically discuss the application of prior biological knowledge present in databases to the interpretation of mGWAS results and discuss the potential of mathematical models. As the technology continuously improves to detect metabolites and to measure genetic variation, it is clear that comprehensive systems biology based approaches are required to further our insight in the association between genes, metabolites and disease. This article is part of a Special Issue entitled: From Genome to Function.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Harish
authors.initials: H
authors.lastname: Dharuri
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands; Genetic Epidemiology Unit, Departments of Epidemiology and Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Ayşe
authors.initials: A
authors.lastname: Demirkan
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Jan Bert
authors.initials: JB
authors.lastname: van Klinken
authors.affiliation: Department of Endocrinology, Leiden University Medical Center, Leiden, Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands; Department of Physiology and Biophysics, Weill Cornell Medical College-Qatar, Doha, Qatar.
authors.forename: Dennis Owen
authors.initials: DO
authors.lastname: Mook-Kanamori
authors.affiliation: Genetic Epidemiology Unit, Departments of Epidemiology and Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands; Department of Endocrinology, Leiden University Medical Center, Leiden, Netherlands. Electronic address: KoWvD@lumc.nl.
authors.forename: Ko
authors.initials: K
authors.lastname: Willems van Dijk
keywords: Analysis; Genome-wide association studies (GWAS); Metabolomics; Pathway; Systems biology