The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Tove Fall*, Sara Hagg, Reedik Maegi, 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, Renee F. A. G. de Bruijn, M. Arfan Ikram, Najaf Amin, Anthony J. Balmforth, Peter S. Braund, Alexander S. F. Doney, Angela Doering, Paul Elliott, Tonu Esko, Oscar H. Franco, Solveig Gretarsdottir, Anna-Liisa Hartikainen, Kauko Heikkila, Karl-Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hypponen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Martin D. Tobin, George Davey Smith, ENGAGE Consortium

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

159 Citations (Scopus)


Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

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 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared 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

Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

Original languageEnglish
Article number1001474
Number of pages15
JournalPLoS Medicine
Issue number6
Publication statusPublished - Jun 2013


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