• Peter Würtz, Qin Wang, Antti J Kangas, Rebecca C Richmond, Joni Skarp, Mika Tiainen, Tuulia Tynkkynen, Pasi Soininen, Aki S Havulinna, Marika Kaakinen, Jorma S Viikari, Markku J Savolainen, Mika Kähönen, Terho Lehtimäki, Satu Männistö, Stefan Blankenberg, Tanja Zeller, Jaana Laitinen, Anneli Pouta, Pekka Mäntyselkä, Mauno Vanhala, Paul Elliott, Kirsi H Pietiläinen, Samuli Ripatti, Veikko Salomaa, Olli T Raitakari, Marjo-Riitta Järvelin, George Davey Smith, and Mika Ala-Korpela.
• Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
• PLoS Med. 2014 Dec 1; 11 (12): e1001765.

BackgroundIncreased adiposity is linked with higher risk for cardiometabolic diseases. We aimed to determine to what extent elevated body mass index (BMI) within the normal weight range has causal effects on the detailed systemic metabolite profile in early adulthood.Methods And FindingsWe used Mendelian randomization to estimate causal effects of BMI on 82 metabolic measures in 12,664 adolescents and young adults from four population-based cohorts in Finland (mean age 26 y, range 16-39 y; 51% women; mean ± standard deviation BMI 24 ± 4 kg/m(2)). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. In cross-sectional analyses, elevated BMI was adversely associated with cardiometabolic risk markers throughout the systemic metabolite profile, including lipoprotein subclasses, fatty acid composition, amino acids, inflammatory markers, and various hormones (p<0.0005 for 68 measures). Metabolite associations with BMI were generally stronger for men than for women (median 136%, interquartile range 125%-183%). A gene score for predisposition to elevated BMI, composed of 32 established genetic correlates, was used as the instrument to assess causality. Causal effects of elevated BMI closely matched observational estimates (correspondence 87% ± 3%; R(2)= 0.89), suggesting causative influences of adiposity on the levels of numerous metabolites (p<0.0005 for 24 measures), including lipoprotein lipid subclasses and particle size, branched-chain and aromatic amino acids, and inflammation-related glycoprotein acetyls. Causal analyses of certain metabolites and potential sex differences warrant stronger statistical power. Metabolite changes associated with change in BMI during 6 y of follow-up were examined for 1,488 individuals. Change in BMI was accompanied by widespread metabolite changes, which had an association pattern similar to that of the cross-sectional observations, yet with greater metabolic effects (correspondence 160% ± 2%; R(2) = 0.92).ConclusionsMendelian randomization indicates causal adverse effects of increased adiposity with multiple cardiometabolic risk markers across the metabolite profile in adolescents and young adults within the non-obese weight range. Consistent with the causal influences of adiposity, weight changes were paralleled by extensive metabolic changes, suggesting a broadly modifiable systemic metabolite profile in early adulthood. Please see later in the article for the Editors' Summary.

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