Genome-Wide Association Study of Metabolic Traits Reveals Novel Gene-Metabolite-Disease Links

Abstract

Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on 1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10−8) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10−44) and lysine (rs8101881, P = 1.2×10−33), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.

Multilayered Genetic and Omics Dissection of Mitochondrial Activity in a Mouse Reference Population

“…In this diverse population, which includes~30 BXD strains (with only one strain overlapping with those in our study), 2-AA is diminished in cohorts with higher fasted glucose (Figure 5F), and the two are again negatively correlated (Figure S2E). Likewise, we observed the same trend in a human population study (Cohorte Lausannoise [CoLaus] study [Firmann et al, 2008]), in which we recently analyzed the spot urine samples of 835 middle-aged or elderly individuals (Rueedi et al, 2014). In this cohort, diabetic patients (Figure S2E) also displayed a marked decrease in 2-AA levels (Figure 5F).…”

“…Strikingly, we replicated this association between 2-AA and high glucose levels in a recent and completely independent metabolomic data set collected in the Hybrid Mouse Diversity Panel (Ghazalpour et al, 2014). Furthermore, and clinically relevant, we demonstrated in a human population-based sample, Co-Laus, that diabetic patients likewise have lower urinary levels of 2-AA (Rueedi et al, 2014). Thus, 2-AA levels are consistently linked to the diabetes status in both mice and humans, and in the BXDs we can unequivocally attribute a causal part of this variance to variants in Dhtkd1 .…”

“…All study participants gave written consent. Full details of the human NMR metabolomics data are in a separate parallel publication (Rueedi et al, 2014). …”

Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations

“…The locus associated with 1-ribosyl-imidazoleacetate included brain eQTLs for several genes, including NAPRT, which encodes an enzyme (nicotinate phosphoribosyltransferase) involved in transferring ribosyl groups 55 . The locus for N6-methyllysine includes brain eQTLs for the PYROXD2 gene, which has been associated with other metabolites (trimethylamine and dimethylamine) in previous studies 50,56,57 . The locus associated with N-acetylglutamate included a brain eQTL for the SLC13A3 gene that encodes sodium-dependent dicarboxylate cotransporter 3, which has been implicated as a transporter for N-acetylglutamate and for N-carbamoylglutamate, a drug used to treat N-acetylglutamate synthase deficiency 58 .…”

Pharmacometabonomics in Humans: A New Tool for Personalized Medicine

“…Just one example of the potential of this approach is provided by a GWAS--metabonomics study of metabolic traits associated with SNPs found in 835 Caucasian participants on the CoLaus study. [62] A key finding was of an association between urinary fucose levels and the presence of SNP rs492602 in the FUT2 gene, which encodes a fucosyltransferase enzyme. The FUT2 gene has already been associated with Crohn's disease, and it was proposed that elevated urinary fucose could be a biomarker for the dysbiosis associated with Crohn's disease, especially as fucose is known to influence human microbiome composition.…”