title: Human metabolic profiles are stably controlled by genetic and environmental variation.
abstract: ¹H Nuclear Magnetic Resonance spectroscopy (¹H NMR) is increasingly used to measure metabolite concentrations in sets of biological samples for top-down systems biology and molecular epidemiology. For such purposes, knowledge of the sources of human variation in metabolite concentrations is valuable, but currently sparse. We conducted and analysed a study to create such a resource. In our unique design, identical and non-identical twin pairs donated plasma and urine samples longitudinally. We acquired ¹H NMR spectra on the samples, and statistically decomposed variation in metabolite concentration into familial (genetic and common-environmental), individual-environmental, and longitudinally unstable components. We estimate that stable variation, comprising familial and individual-environmental factors, accounts on average for 60% (plasma) and 47% (urine) of biological variation in ¹H NMR-detectable metabolite concentrations. Clinically predictive metabolic variation is likely nested within this stable component, so our results have implications for the effective design of biomarker-discovery studies. We provide a power-calculation method which reveals that sample sizes of a few thousand should offer sufficient statistical precision to detect ¹H NMR-based biomarkers quantifying predisposition to disease.
authors: Department of Statistics, University of Oxford, Oxford, UK. nicholso@stats.ox.ac.uk
authors: George
authors: G
authors: Nicholson
authors: Mattias
authors: M
authors: Rantalainen
authors: Anthony D
authors: AD
authors: Maher
authors: Jia V
authors: JV
authors: Li
authors: Daniel
authors: D
authors: Malmodin
authors: Kourosh R
authors: KR
authors: Ahmadi
authors: Johan H
authors: JH
authors: Faber
authors: Ingileif B
authors: IB
authors: Hallgrímsdóttir
authors: Amy
authors: A
authors: Barrett
authors: Henrik
authors: H
authors: Toft
authors: Maria
authors: M
authors: Krestyaninova
authors: Juris
authors: J
authors: Viksna
authors: Sudeshna Guha
authors: SG
authors: Neogi
authors: Marc-Emmanuel
authors: ME
authors: Dumas
authors: Ugis
authors: U
authors: Sarkans
authors: The Molpage Consortium
authors: Bernard W
authors: BW
authors: Silverman
authors: Peter
authors: P
authors: Donnelly
authors: Jeremy K
authors: JK
authors: Nicholson
authors: Maxine
authors: M
authors: Allen
authors: Krina T
authors: KT
authors: Zondervan
authors: John C
authors: JC
authors: Lindon
authors: Tim D
authors: TD
authors: Spector
authors: Mark I
authors: MI
authors: McCarthy
authors: Elaine
authors: E
authors: Holmes
authors: Dorrit
authors: D
authors: Baunsgaard
authors: Chris C
authors: CC
authors: Holmes
mesh_terms: D000368:Aged; D000465:Algorithms; D015415:Biomarkers / Q000097:blood / Q000652:urine; D030541:Databases, Genetic; D005260:Female; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D006801:Humans; D055442:Metabolome / Q000235:genetics*; D008875:Middle Aged; D015233:Models, Statistical; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D012107:Research Design; D018401:Sample Size; D049490:Systems Biology / Q000379:methods*; D014429:Twins, Dizygotic / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics; D044465:White People / Q000235:genetics*
chemical_list: D015415:Biomarkers