title: Metabolic signatures of adiposity in young adults: Mendelian randomization analysis and effects of weight change.
abstract: BACKGROUND
  Increased 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.
  
  
  RESULTS
  We 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).
  
  
  CONCLUSIONS
  Mendelian 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.
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Peter
authors.initials: P
authors.lastname: Würtz
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Kangas
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Richmond
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.
authors.forename: Joni
authors.initials: J
authors.lastname: Skarp
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Tiainen
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Tynkkynen
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Aki S
authors.initials: AS
authors.lastname: Havulinna
authors.affiliation: Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Marika
authors.initials: M
authors.lastname: Kaakinen
authors.affiliation: Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Jorma S
authors.initials: JS
authors.lastname: Viikari
authors.affiliation: Department of Internal Medicine, Clinical Research Center and Biocenter Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors.forename: Markku J
authors.initials: MJ
authors.lastname: Savolainen
authors.affiliation: Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, Tampere, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Männistö
authors.affiliation: University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.affiliation: University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.affiliation: Finnish Institute of Occupational Health, Helsinki, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Laitinen
authors.affiliation: Department of Obstetrics and Gynecology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.affiliation: Primary Health Care, School of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Mäntyselkä
authors.affiliation: Primary Health Care, School of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; Primary Health Care, Central Finland Central Hospital, Jyväskylä, Finland.
authors.forename: Mauno
authors.initials: M
authors.lastname: Vanhala
authors.affiliation: Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, Imperial College London, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Kirsi H
authors.initials: KH
authors.lastname: Pietiläinen
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.affiliation: Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, Imperial College London, London, United Kingdom; Oulu University Hospital, Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Oulu University Hospital, Oulu, Finland; Computational Medicine, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Mika
authors.initials: M
authors.lastname: Ala-Korpela
mesh_terms: D050154:Adiposity / Q000502:physiology*; D000328:Adult; D015992:Body Mass Index; D001835:Body Weight / Q000502:physiology*; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods*; D055815:Young Adult