title: A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection.
abstract: We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H 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 (1)H 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.
authors.affiliation: Department of Statistics, University of Oxford, Oxford, United Kingdom. nicholso@stats.ox.ac.uk
authors.forename: George
authors.initials: G
authors.lastname: Nicholson
authors.forename: Mattias
authors.initials: M
authors.lastname: Rantalainen
authors.forename: Jia V
authors.initials: JV
authors.lastname: Li
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Maher
authors.forename: Daniel
authors.initials: D
authors.lastname: Malmodin
authors.forename: Kourosh R
authors.initials: KR
authors.lastname: Ahmadi
authors.forename: Johan H
authors.initials: JH
authors.lastname: Faber
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.forename: N William
authors.initials: NW
authors.lastname: Rayner
authors.forename: Henrik
authors.initials: H
authors.lastname: Toft
authors.forename: Maria
authors.initials: M
authors.lastname: Krestyaninova
authors.forename: Juris
authors.initials: J
authors.lastname: Viksna
authors.forename: Sudeshna Guha
authors.initials: SG
authors.lastname: Neogi
authors.forename: Marc-Emmanuel
authors.initials: ME
authors.lastname: Dumas
authors.forename: Ugis
authors.initials: U
authors.lastname: Sarkans
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.forename: Maxine
authors.initials: M
authors.lastname: Allen
authors.forename: Krina T
authors.initials: KT
authors.lastname: Zondervan
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: John C
authors.initials: JC
authors.lastname: Lindon
authors.forename: Dorrit
authors.initials: D
authors.lastname: Baunsgaard
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Chris C
authors.initials: CC
authors.lastname: Holmes
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D004123:Dimethylamines / Q000097:blood / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D058610:Isobutyrates / Q000378:metabolism / Q000652:urine; D009682:Magnetic Resonance Spectroscopy; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D055442:Metabolome / Q000235:genetics*; D008744:Methylamines / Q000378:metabolism / Q000652:urine; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: D004123:Dimethylamines; D058610:Isobutyrates; D008744:Methylamines; C034516:dimethylamine; D000123:Acetyltransferases; C116373:NAT8 protein, human; C023336:trimethylamine