PLoS Medicine (Jan 2013)

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 Rivera,
  • Kati 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,
  • Lennart C Karssen,
  • Johannes Kettunen,
  • Wolfgang Koenig,
  • Kari Kuulasmaa,
  • Tiina Laatikainen,
  • Jaana Laitinen,
  • Cecilia Lindgren,
  • Valeriya Lyssenko,
  • Esa Läärä,
  • Nigel W Rayner,
  • Satu Männistö,
  • Anneli Pouta,
  • Wolfgang Rathmann,
  • Fernando Rivadeneira,
  • Aimo Ruokonen,
  • Markku J Savolainen,
  • Eric J G Sijbrands,
  • Kerrin S Small,
  • Jan H Smit,
  • Valgerdur Steinthorsdottir,
  • Ann-Christine Syvänen,
  • Anja Taanila,
  • Martin D Tobin,
  • Andre G Uitterlinden,
  • Sara M Willems,
  • Gonneke Willemsen,
  • Jacqueline Witteman,
  • Markus Perola,
  • Alun Evans,
  • Jean Ferrières,
  • Jarmo Virtamo,
  • Frank Kee,
  • David-Alexandre Tregouet,
  • Dominique Arveiler,
  • Philippe Amouyel,
  • Marco M Ferrario,
  • Paolo Brambilla,
  • Alistair S Hall,
  • Andrew C Heath,
  • Pamela A F Madden,
  • Nicholas G Martin,
  • Grant W Montgomery,
  • John B Whitfield,
  • Antti Jula,
  • Paul Knekt,
  • Ben Oostra,
  • Cornelia M van Duijn,
  • Brenda W J H Penninx,
  • George Davey Smith,
  • Jaakko Kaprio,
  • Nilesh J Samani,
  • Christian Gieger,
  • Annette Peters,
  • H Erich Wichmann,
  • Dorret I Boomsma,
  • Eco J C de Geus,
  • TiinaMaija Tuomi,
  • Chris Power,
  • Christopher J Hammond,
  • Tim D Spector,
  • Lars Lind,
  • Marju Orho-Melander,
  • Colin Neil Alexander Palmer,
  • Andrew D Morris,
  • Leif Groop,
  • Marjo-Riitta Järvelin,
  • Veikko Salomaa,
  • Erkki Vartiainen,
  • Albert Hofman,
  • Samuli Ripatti,
  • Andres Metspalu,
  • Unnur Thorsteinsdottir,
  • Kari Stefansson,
  • Nancy L Pedersen,
  • Mark I McCarthy,
  • Erik Ingelsson,
  • Inga Prokopenko,
  • European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium

DOI
https://doi.org/10.1371/journal.pmed.1001474
Journal volume & issue
Vol. 10, no. 6
p. e1001474

Abstract

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BackgroundThe 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 findingsWe 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 ConclusionsWe provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.