A genome-wide metabolic QTL analysis in europeans implicates two Loci shaped by recent positive selection

George Nicholson, Mattias Rantalainen, Jia V. Li, Anthony D. Maher, Daniel Malmodin, Kourosh R. Ahmadi, Johan H. Faber, Amy Barrett, Josine L. Min, N. William Rayner, Henrik Toft, Maria Krestyaninova, Juris Viksna, Sudeshna Guha Neogi, Marc Emmanuel Dumas, Ugis Sarkans, Peter Donnelly, Thomas Illig, Jerzy Adamski, Karsten SuhreMaxine Allen, Krina T. Zondervan, Tim D. Spector, Jeremy K. Nicholson, John C. Lindon, Dorrit Baunsgaard, Elaine Holmes, Mark I. McCarthy, Chris C. Holmes

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82 Citations (Scopus)


We have performed a metabolite quantitative trait locus (mQTL) study of the 1H nuclear magnetic resonance spectroscopy ( 1H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by 1H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10 -11<p<2.8×10 -23). Three of these-trimethylamine, 3-amino-isobutyrate, and an N-acetylated compound-were measured in urine. The other-dimethylamine-was measured in plasma. Trimethylamine and dimethylamine mapped to a single genetic region (hence we report a total of three implicated genomic regions). Two of the three hit regions lie within haplotype blocks (at 2p13.1 and 10q24.2) that carry the genetic signature of strong, recent, positive selection in European populations. Genes NAT8 and PYROXD2, both with relatively uncharacterized functional roles, are good candidates for mediating the corresponding mQTL associations. The study's longitudinal twin design allowed detailed variance-components analysis of the sources of population variation in metabolite levels. The mQTLs explained 40%-64% of biological population variation in the corresponding metabolites' concentrations. These effect sizes are stronger than those reported in a recent, targeted mQTL study of metabolites in serum using the targeted-metabolomics Biocrates platform. By re-analysing our plasma samples using the Biocrates platform, we replicated the mQTL findings of the previous study and discovered a previously uncharacterized yet substantial familial component of variation in metabolite levels in addition to the heritability contribution from the corresponding mQTL effects.

Original languageEnglish
Article numbere1002270
JournalPLoS Genetics
Issue number9
Publication statusPublished - Sep 2011
Externally publishedYes


ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Nicholson, G., Rantalainen, M., Li, J. V., Maher, A. D., Malmodin, D., Ahmadi, K. R., Faber, J. H., Barrett, A., Min, J. L., Rayner, N. W., Toft, H., Krestyaninova, M., Viksna, J., Neogi, S. G., Dumas, M. E., Sarkans, U., Donnelly, P., Illig, T., Adamski, J., ... Holmes, C. C. (2011). A genome-wide metabolic QTL analysis in europeans implicates two Loci shaped by recent positive selection. PLoS Genetics, 7(9), [e1002270]. https://doi.org/10.1371/journal.pgen.1002270