The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
Fall T., Hägg S., Mägi R., Ploner A., Fischer K., Horikoshi M., Sarin A-P., Thorleifsson G., Ladenvall C., Kals M., Kuningas M., Draisma HHM., Ried JS., van Zuydam NR., Huikari V., Mangino M., Sonestedt E., Benyamin B., Nelson CP., Rivera NV., Kristiansson K., Shen H-Y., Havulinna AS., Dehghan A., Donnelly LA., Kaakinen M., Nuotio M-L., Robertson N., de Bruijn RFAG., Ikram MA., Amin N., Balmforth AJ., Braund PS., Doney ASF., Döring A., Elliott P., Esko T., Franco OH., Gretarsdottir S., Hartikainen A-L., Heikkilä K., Herzig K-H., Holm H., Hottenga JJ., Hyppönen E., Illig T., Isaacs A., Isomaa B., Karssen LC., Kettunen J., Koenig W., Kuulasmaa K., Laatikainen T., Laitinen J., Lindgren C., Lyssenko V., Läärä E., Rayner NW., Männistö S., Pouta A., Rathmann W., Rivadeneira F., Ruokonen A., Savolainen MJ., Sijbrands EJG., Small KS., Smit JH., Steinthorsdottir V., Syvänen A-C., Taanila A., Tobin MD., Uitterlinden AG., Willems SM., Willemsen G., Witteman J., Perola M., Evans A., Ferrières J., Virtamo J., Kee F., Tregouet D-A., Arveiler D., Amouyel P., Ferrario MM., Brambilla P., Hall AS., Heath AC., Madden PAF., Martin NG., Montgomery GW., Whitfield JB., Jula A., Knekt P., Oostra B., van Duijn CM., Penninx BWJH., Smith GD., Kaprio J., Samani NJ., Gieger C., Peters A., Wichmann HE., Boomsma DI., de Geus EJC., Tuomi T., Power C., Hammond CJ., Spector TD., Lind L., Orho-Melander M., Palmer CNA., Morris AD., Groop L., Järvelin M-R., Salomaa V., Vartiainen E., Hofman A., Ripatti S., Metspalu A., Thorsteinsdottir U., Stefansson K., Pedersen NL., McCarthy MI., Ingelsson E., Prokopenko I., European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium None.
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.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 < 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).We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.