Evidence from genetic and molecular investigations strongly suggests an etiological relationship between asthma and obesity. Genome-wide association studies (GWAS) have identified common risk loci for these diseases, which share alterations in immunological mechanisms and changes in both gut microbiome architecture and microbial metabolites. These observations suggest evidence of cross phenotype associations (pleiotropy) in asthma and obesity. We aim to define new biological mechanisms underlying common risk of asthma and obesity through combined genetic and metabolomic analyses in the Epidemiological study on the Genetics and Environment of Asthma (EGEA, n=1,400), followed by similar analyses in an independent cohort (the Saguenay-Lac-Saint-Jean, SLSJ n=1,200) to assess robustness of results and by characterisation of the biological roles of metabolites associated with asthma and obesity in a mouse model relevant to these diseases. Metabolomic profiling will apply both untargeted approaches (1H-Nuclear Magnetic Resonance -NMR and mass spectrometry -MS), which will generate quantitative data for about 5,000 (MS) and 15,000 (NMR) spectral signals, and a targeted platform (Metabolon), which will assist metabolite attribution in NMR and MS datasets. We will carry out metabolome wide association studies (MWAS) to test associations between metabolites and asthma and adiposity phenotypes, examined jointly, in EGEA in order to define biomarkers associated with these two phenotypes. We will take advantage of SNP-based genome-wide genotype data already available in EGEA to carry out GWAS of metabolome quantitative data in order to localise genes associated with changes in metabolite abundance and underlying shared risk of asthma and adiposity. We will apply Mendelian randomization methods to identify metabolites with a causal effect on asthma and adiposity. Follow up metabolome and genetic analyses will be carried out in SLSJ in order to assess robustness of results from MWAS and GWAS in EGEA. Finally, the concepts elaborated in humans will be tested in vivo in a mouse model of asthma and obesity induced experimentally, which will be treated chronically by candidate metabolites in order to test their biological effects on obesity and asthma endophenotypes and analyse molecular (metabolome, transcriptome) consequences. Ultimately, METABASTHMA will add new and relevant components to existing asthma genetics and epidemiology by generating full resolution metabolomic profiles from individuals with asthma accompanying inflammation and obesity. It will deliver novel knowledge of diagnostic metabolic biomarkers, including metabolic products of gut microbial activity, at the crossroads between host susceptibility alleles, lifestyle and environmental exposures that will provide a framework to predict risk of asthma and obesity.