Quantitative Genetics and Network Biology of Metabolic Profiles

The study of human multifactorial diseases like cancer, diabetes, obesity or cardiovascular disease and complex biological processes such as ageing, represents a real healthcare challenge for the western and developing world.

Regulation of metabolism and signalling is a key biological phenomenon in these conditions and the field of metabonomics has now made a significant impact in functional genomics, owing to serendipitous biomarker discovery in model organisms and in human populations, as well as candidate-driven approaches. In large-scale epidemiological studies (n>1,000), association between metabolic phenotypes and disease phenotypes gave rise to Metabolome-Wide Association Studies (MWAS).

However, the study of the genetics of metabolic profiles is a wide area, ranging from characterizing genetically-engineered model organisms or inborn errors of metabolism to the quantitative study of metabolic phenotypes in segregating populations. Quantitative Trait Locus (QTL) mapping of metabolomic traits (mQTL), and Metabolome-Wide Genome-Wide Association Studies (MW-GWAS) are robust and accurate strategies for the integration of genome-wide genotyping and metabolome-wide profiling by ¹H NMR and MS, identifying candidate biomarkers and susceptibility genes. 

Finally, to enhance our understanding in the genetic regulation of such complex metabolic patterns in a network biology framework, candidate genes and metabolic biomarkers are mapped onto biological networks such as metabolic pathways or protein-protein interaction networks to identify key regulatory proteins explaining the influence of gene variants on metabolic profiles and eventually disease phenotypes. Recent developments such as Metabolite-Set Enrichment Analysis (MSEA) or integrated Metabolome Interactome Mapping (iMIM) allow a better mechanistic understanding of metabolic phenotypes. 

 

Contact: Dr. Marc E. Dumas: m.dumas@imperial.ac.uk 

Key Projects

• FGENTCARD (2007 - 2010)
• EURATRANS (2010 - 2014)

Key Recent PublicationsCazier JB; Kaisaki PJ; Argoud K; Blaise BJ; Veselkov K; Ebbels TM; Tsamg TM; Wang Y; . (26 Oct 2011). Untargeted Metabolome Quantitative Trait Locus Mapping Associates Variation in Urine Glycerate to Mutant Glycerate Kinase. J Proteome Res. DOI.

• Cazier JB, Kaisaki PJ, Argoud K, Blaise BJ, Veselkov K, Ebbels TM, Tsang TM, Wang Y, Bihoreau MT, Mitchell SC, Holmes E, Lindon JC, Scott J, Nicholson JK, Dumas ME, Gauguier D. Untargeted Metabolome Quantitative Trait Locus Mapping Associates Variation in Urine Glycerate to Mutant Glycerate Kinase. J Proteome Res 2011 Oct 26. [Epub ahead of print].
• Davidovic L, Navratil V, Bonaccorso CM, Catania MV, Bardoni B, Dumas ME. A metabolomic and systems biology perspective on the brain of the fragile X syndrome mouse model. Genome Res, 2011 Sep 7. [Epub ahead of print].
• Nicholson G, Rantalainen M, Li JV, Maher AD, Malmodin D, Ahmadi KR, Faber JH, Min JL, William Rayner N, Toft H, Krestyaninova M, Viksna J, Guha Neogi S, Dumas ME, Sarkans U, Donnelly P, Allen M, Zondervan KT, Spector TD, Nicholson JK, Lindon JC, Baunsgaard D, Holmes EC, McCarthy MI, Holmes CC and MolPAGE consortium. A genome-wide metabolic QTL analysis in Europeans identifies functional effects of two loci shaped by recent positive selection. PLoS Genetics 2011;7(9):e1002270.
• 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, Silverman BW, Donnelly P, Nicholson JK, Allen M, Zondervan KT, Lindon JC, Spector TD, McCarthy MI, Holmes E, Baunsgaard D, Holmes CC.  Human metabolic profiles are stably controlled by genetic and environmental variation. Molecular Systems Biology 2011;7:525.
• Pontoizeau C, Fearnside J, Navratil V, Domange C, Cazier JB, Fernandez-Santamaria C, Kaisaki PJ, Emsley L, Toulhoat P, Bihoreau MT, Nicholson JK, Gauguier D, Dumas ME. Broad-range natural metabotype variation drives physiological plasticity in control healthy inbred rat strains. J Proteome Res.  2011;10:1675-1689. DOI.
• Claus SP, Ellero S, Berger B, Krause L,  Bruttin A , Molina A, Paris A, Want E, De Waziers I, Cloarec O, Richards S, Wang Y, Dumas ME, Ross A, Rezzi S, Kochhar S Van Bladeren P, Lindon J, Holmes E, Nicholson JK. Colonization-induced host-gut microbial metabolic interaction. mBio 2011; 2(2):e00271-10. doi:10.1128/mBio.00271-10. DOI.
• Fearnside JF, Dumas ME, Rothwell AR, Wilder SP, Cloarec O, Toye A, Blancher C, Holmes E, Tatoud R, Barton RH and others. Phylometabonomic patterns of adaptation to high fat diet feeding in inbred mice. PLoS ONE 2008;3(2):e1668. DOI.
• Dumas ME, Wilder SP, Bihoreau MT, Barton RH, Fearnside JF, Argoud K, D'Amato L, Wallis RH, Blancher C, Keun HC and others. Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models. Nat Genet 2007;39(5):666-72. DOI.