Current status on genome-metabolome-wide associations: an opportunity in nutrition research - PubMed (original) (raw)

Current status on genome-metabolome-wide associations: an opportunity in nutrition research

Ivan Montoliu et al. Genes Nutr. 2013 Jan.

Abstract

Genome-wide association studies (GWASs) have become a very important tool to address the genetic origin of phenotypic variability, in particular associated with diseases. Nevertheless, these types of studies provide limited information about disease etiology and the molecular mechanisms involved. Recently, the incorporation of metabolomics into the analysis has offered novel opportunities for a better understanding of disease-related metabolic deregulation. The pattern emerging from this work is that gene-driven changes in metabolism are prevalent and that common genetic variations can have a profound impact on the homeostatic concentrations of specific metabolites. A particularly interesting aspect of this work takes into account interactions of environment and lifestyle with the genome and how this interaction translates into changes in the metabolome. For instance, the role of PYROXD2 in trimethylamine metabolism points to an interaction between host and microbiome genomes (host/microbiota). Often, these findings reveal metabolic deregulations, which could eventually be tuned with a nutritional intervention. Here we review the development of gene-metabolism association studies from a single-gene/single-metabolite to a genome-wide/metabolome-wide approach and highlight the conceptual changes associated with this ongoing transition. Moreover, we report some of our recent GWAS results on a cohort of 265 individuals from an ethnically diverse population that validate and refine previous findings on gene-urine metabolism interactions. Specifically, our results confirm the effect of PYROXD2 polymorphisms on trimethylamine metabolism and suggest that a previously reported association of N-acetylated compounds with the ALMS1/NAT8 locus is driven by SNPs in the ALMS1 gene.

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Figures

Fig. 1

Fig. 1

a Manhattan plot resulting from a GWAS that uses as input phenotype the intensity of a 1H-NMR chemical shift centered at 2.032 ppm. This chemical shift peak has been assigned to an _N_-acetylated compound, possibly _N_-acetylated proteins. The plot shows a strong association with a large number of SNPs on chromosome 2. A close-up (b) of the genomic regions shows that the center of the association peak lies clearly on the ALMS1 gene and not on the neighboring NAT8 gene. The QQ-plot (c) shows that a large number of SNPs are strongly associated with this compound. The fact that all the significant associations come from the same locus (panela and b) underlines the existence of strong LD in this genome region

Fig. 2

Fig. 2

a Manhattan plot resulting from a GWAS that uses as input phenotype the intensity in 1H-NMR chemical shift centered at 2.856 ppm. This chemical shift peak has been assigned to Trimethyl-amine. The plot shows a strong association with a series of SNPs on chromosome 10. These SNPs are located in or around the gene PYROXD2, which encodes a probable pyridine nucleotide-disulfide oxidoreductase. b QQ-plot corresponding to the Manhattan plot shown in subfigure (a). The plot underlines the significance of the association and indicates that the strength of the association is not driven by lambda inflation

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