Human metabolic profiles are stably controlled by genetic and environmental variation.
Nicholson G., Rantalainen M., Maher AD., Li JV., Malmodin D., Ahmadi KR., Faber JH., Hallgrímsdóttir IB., Barrett A., Toft H., Krestyaninova M., Viksna J., Neogi SG., Dumas ME., Sarkans U., The Molpage Consortium None., Silverman BW., Donnelly P., Nicholson JK., Allen M., Zondervan KT., Lindon JC., Spector TD., McCarthy MI., Holmes E., Baunsgaard D., Holmes CC.
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.