The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis

Tove Fall, Sara Hägg, Reedik Mägi, Alexander Ploner, Krista Fischer, Momoko Horikoshi, Antti-Pekka Sarin, Gudmar Thorleifsson, Claes Ladenvall, Mart Kals, Maris Kuningas, Harmen H M Draisma, Janina S Ried, Natalie R van Zuydam, Ville Huikari, Massimo Mangino, Emily Sonestedt, Beben Benyamin, Christopher P Nelson, Natalia V RiveraKati Kristiansson, Huei-Yi Shen, Aki S Havulinna, Abbas Dehghan, Louise A Donnelly, Marika Kaakinen, Marja-Liisa Nuotio, Neil Robertson, Renée F A G de Bruijn, M Arfan Ikram, Najaf Amin, Anthony J Balmforth, Peter S Braund, Alexander S F Doney, Angela Döring, Paul Elliott, Tõnu Esko, Oscar H Franco, Solveig Gretarsdottir, Anna-Liisa Hartikainen, Kauko Heikkilä, Karl-Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hyppönen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Alun Evans, Frank Kee, European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium

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Background: The association between adiposity and cardiometabolic traits is well known from epidemiologicalstudies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determinewhether adiposity is causally related to various cardiometabolic traits using the Mendelian randomizationapproach.Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators we recompared to the BMI–trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03–1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1–1.4; all p,0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p,0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as betweenadiposity and increased liver enzymes.
Original languageEnglish
Article numbere1001474
Number of pages15
JournalPLoS Medicine
Issue number6
Publication statusPublished - 25 Jun 2013


  • Adiposity
  • Body Mass Index
  • Cardiovascular Diseases
  • Case-Control Studies
  • Confounding Factors (Epidemiology)
  • Genetic Association Studies
  • Humans
  • Mendelian Randomization Analysis
  • Meta-Analysis as Topic
  • Polymorphism, Single Nucleotide
  • Proteins
  • Quantitative Trait, Heritable


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