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Cited by 203Genetic Associations and EpidemiologyAdipokines, Inflammation, and Metabolic DiseasesCardiovascular Disease and Adiposity

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

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Fall, Tove, Hägg, Sara, Mägi, Reedik, Ploner, Alexander, Fischer, Krista, Horikoshi, Momoko, Sarin, Antti-Pekka, Thorleifsson, Gudmar, Ladenvall, Claes, Kals, Mart, Kuningas, Maris, Draisma, Harmen H. M., Ried, Janina S., van Zuydam, Natalie R., Huikari, Ville, Mangino, Massimo, Sonestedt, Emily, Benyamin, Beben, Nelson, Christopher P., Rivera, Natalia V., Kristiansson, Kati, Shen, Huei-yi, Havulinna, Aki S., Dehghan, Abbas, Donnelly, Louise A., Kaakinen, Marika, Nuotio, Marja-Liisa, Robertson, Neil, de Bruijn, Renée F. A. G., Ikram, M. Arfan, Amin, Najaf, Balmforth, Anthony J., Braund, Peter S., Doney, Alexander S. F., Döring, Angela, Elliott, Paul, Esko, Tõnu, Franco, Oscar H., Gretarsdottir, Solveig, Hartikainen, Anna-Liisa, Heikkilä, Kauko, Herzig, Karl-Heinz, Holm, Hilma, Hottenga, Jouke Jan, Hyppönen, Elina, Illig, Thomas, Isaacs, Aaron, Isomaa, Bo, Karssen, Lennart C., Kettunen, Johannes, Koenig, Wolfgang, Kuulasmaa, Kari, Laatikainen, Tiina, Laitinen, Jaana, Lindgren, Cecilia, Lyssenko, Valeriya, Läärä, Esa, Rayner, Nigel W., Männistö, Satu, Pouta, Anneli, Rathmann, Wolfgang, Rivadeneira, Fernando, Ruokonen, Aimo, Savolainen, Markku J., Sijbrands, Eric J. G., Small, Kerrin S., Smit, Jan H., Steinthorsdottir, Valgerdur, Syvänen, Ann-Christine, Taanila, Anja, Tobin, Martin D., Uitterlinden, Andre G., Willems, Sara M., Willemsen, Gonneke, Witteman, Jacqueline, Perola, Markus, Evans, Alun, Ferrières, Jean, Virtamo, Jarmo, Kee, Frank, Tregouet, David-Alexandre, Arveiler, Dominique, Amouyel, Philippe, Ferrario, Marco M., Brambilla, Paolo, Hall, Alistair S., Heath, Andrew C., Madden, Pamela A. F., Martin, Nicholas G., Montgomery, Grant W., Whitfield, John B., Jula, Antti, Knekt, Paul, Oostra, Ben, van Duijn, Cornelia M., Penninx, Brenda W. J. H., Davey Smith, George, Kaprio, Jaakko, Samani, Nilesh J., Gieger, Christian, Peters, Annette, Wichmann, H.-Erich, Boomsma, Dorret I., de Geus, Eco J. C., Tuomi, TiinaMaija, Power, Chris, Hammond, Christopher J., Spector, Tim D., Lind, Lars, Orho-Melander, Marju, Palmer, Colin Neil Alexander, Morris, Andrew D., Groop, Leif, Järvelin, Marjo-Riitta, Salomaa, Veikko, Vartiainen, Erkki, Hofman, Albert, Ripatti, Samuli, Metspalu, Andres, Thorsteinsdottir, Unnur, Stefansson, Kari, Pedersen, Nancy L., McCarthy, Mark I., Ingelsson, Erik, Prokopenko, Inga, for the European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium·2013·PLoS Medicine
DOI 10.1371/journal.pmed.1001474PMC PMC3692470
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Abstract

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 < 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 between adiposity and increased liver enzymes.

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Figure 1 In a Mendelian randomization framework, genotype–phenotype association is assumed to be independent of confounding factors. (A) In an example from our study, the IV estimator is calculated as the beta coefficient from the association of FTO with systolic blood pressure divided by the beta coefficient from the association of FTO with BMI (IV estimator = 0.32/0.36 = 0.89 mm Hg/BMI unit). The IV estimator is equivalent to what is seen when systolic blood pressure is regressed on BMI. These results are supportive of a causal, non-confounded relationship. For binary traits, the calculation of the IV estimator is done on the log-odds scale. (B) The relationship of BMI with T2D, where the IV estimator is ln(ORIV) = ln(1.12)/0.36, which equals a causal OR of BMI for T2D of 1.37. This is larger than what is seen in the standard age- and sex-adjusted logistic regression of T2D on BMI (p = 0.001), indicating that confounding or reverse causation may be present or that BMI measured once in adulthood does not fully reflect the effect of lifetime adiposity.
Figure 1 In a Mendelian randomization framework, genotype–phenotype association is assumed to be independent of confounding factors. (A) In an example from our study, the IV estimator is calculated as the beta coefficient from the association of FTO with systolic blood pressure divided by the beta coefficient from the association of FTO with BMI (IV estimator = 0.32/0.36 = 0.89 mm Hg/BMI unit). The IV estimator is equivalent to what is seen when systolic blood pressure is regressed on BMI. These results are supportive of a causal, non-confounded relationship. For binary traits, the calculation of the IV estimator is done on the log-odds scale. (B) The relationship of BMI with T2D, where the IV estimator is ln(ORIV) = ln(1.12)/0.36, which equals a causal OR of BMI for T2D of 1.37. This is larger than what is seen in the standard age- and sex-adjusted logistic regression of T2D on BMI (p = 0.001), indicating that confounding or reverse causation may be present or that BMI measured once in adulthood does not fully reflect the effect of lifetime adiposity.CC BY · PubMed Central
Figure 2 Association between FTO variant rs9939609 and BMI in 198,502 individuals. The assigned weight for each study in the meta-analysis is shown in percent (% Weight). ES, estimate. For cohort abbreviations and references, see Table S1.
Figure 2 Association between FTO variant rs9939609 and BMI in 198,502 individuals. The assigned weight for each study in the meta-analysis is shown in percent (% Weight). ES, estimate. For cohort abbreviations and references, see Table S1.CC BY · PubMed Central
Figure 3 Association between BMI and incident heart failure in 2,863 cases and 44,400 controls. Estimates (ES) are shown on a hazard ratio scale for a one-unit increase in BMI. The assigned weight for each study in the meta-analysis is shown in percent (% Weight). For cohort abbreviations and references, see Table S1.
Figure 3 Association between BMI and incident heart failure in 2,863 cases and 44,400 controls. Estimates (ES) are shown on a hazard ratio scale for a one-unit increase in BMI. The assigned weight for each study in the meta-analysis is shown in percent (% Weight). For cohort abbreviations and references, see Table S1.CC BY · PubMed Central
Figure 4 Association between FTO and incident heart failure in 2,863 cases and 44,400 controls. Estimates (ES) are shown on a hazard ratio scale per number of effect alleles. The assigned weight for each study in the meta-analysis is shown in percent (% Weight). For cohort abbreviations and references, see Table S1.
Figure 4 Association between FTO and incident heart failure in 2,863 cases and 44,400 controls. Estimates (ES) are shown on a hazard ratio scale per number of effect alleles. The assigned weight for each study in the meta-analysis is shown in percent (% Weight). For cohort abbreviations and references, see Table S1.CC BY · PubMed Central

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Authors
Fall, T., Hägg, S., Mägi, R., Ploner, A., Fischer, K., Horikoshi, M., Sarin, A.-P., Thorleifsson, G., Ladenvall, C., Kals, M., Kuningas, M., Draisma, H. H. M., Ried, J. S., van Zuydam, N. R., Huikari, V., Mangino, M., Sonestedt, E., Benyamin, B., Nelson, C. P., Rivera, N. V., Kristiansson, K., Shen, H.-Y., Havulinna, A. S., Dehghan, A., Donnelly, L. A., Kaakinen, M., Nuotio, M.-L., Robertson, N., de Bruijn, R. F. A. G., Ikram, M. A., Amin, N., Balmforth, A. J., Braund, P. S., Doney, A. S. F., Döring, A., Elliott, P., Esko, T., Franco, O. H., Gretarsdottir, S., Hartikainen, A.-L., Heikkilä, K., Herzig, K.-H., Holm, H., Hottenga, J. J., Hyppönen, E., Illig, T., Isaacs, A., Isomaa, B., Karssen, L. C., Kettunen, J., Koenig, W., Kuulasmaa, K., Laatikainen, T., Laitinen, J., Lindgren, C., Lyssenko, V., Läärä, E., Rayner, N. W., Männistö, S., Pouta, A., Rathmann, W., Rivadeneira, F., Ruokonen, A., Savolainen, M. J., Sijbrands, E. J. G., Small, K. S., Smit, J. H., Steinthorsdottir, V., Syvänen, A.-C., Taanila, A., Tobin, M. D., Uitterlinden, A. G., Willems, S. M., Willemsen, G., Witteman, J., Perola, M., Evans, A., Ferrières, J., Virtamo, J., Kee, F., Tregouet, D.-A., Arveiler, D., Amouyel, P., Ferrario, M. M., Brambilla, P., Hall, A. S., Heath, A. C., Madden, P. A. F., Martin, N. G., Montgomery, G. W., Whitfield, J. B., Jula, A., Knekt, P., Oostra, B., van Duijn, C. M., Penninx, B. W. J. H., Davey Smith, G., Kaprio, J., Samani, N. J., Gieger, C., Peters, A., Wichmann, H.-E., Boomsma, D. I., de Geus, E. J. C., Tuomi, T., Power, C., Hammond, C. J., Spector, T. D., Lind, L., Orho-Melander, M., Palmer, C. N. A., Morris, A. D., Groop, L., Järvelin, M.-R., Salomaa, V., Vartiainen, E., Hofman, A., Ripatti, S., Metspalu, A., Thorsteinsdottir, U., Stefansson, K., Pedersen, N. L., McCarthy, M. I., Ingelsson, E., Prokopenko, I., & for the European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium
Affiliations
  • Uppsala University (SE)
  • Centre for Human Genetics (GB)
  • Karolinska Institutet (SE)
  • University of Tartu (EE)
  • University of Helsinki (FI)
  • Lund University (SE)
  • Erasmus MC (NL)
  • Amsterdam Public Health (NL)
  • Helmholtz Munich (DE)
  • University of Oulu (FI)
  • King's College London (GB)
  • The University of Queensland (AU)
  • University of Leicester (GB)
  • Finnish Institute for Health and Welfare (FI)
  • University of Dundee (GB)
  • University of Leeds (GB)
  • Imperial College London (GB)
  • Kuopio University Hospital (FI)
  • University College London (GB)
  • Folkhälsans Forskningscentrum (FI)
  • Finnish Institute of Occupational Health (FI)
  • Deutsches Diabetes-Zentrum e.V. (DE)
  • Queen's University Belfast (GB)
  • Hôpital Rangueil (FR)
  • Université de Strasbourg (FR)
  • Inserm (FR)
  • University of Milano-Bicocca (IT)
  • Washington University in St. Louis (US)
  • QIMR Berghofer Medical Research Institute (AU)
  • Amsterdam Neuroscience (NL)
Corresponding author
  • Ingelsson, Erik
  • Prokopenko, Inga
ORCID
Venue
PLoS Medicine
Publisher
Public Library of Science (PLoS)
Published
2013-06-25
Volume
10
Issue
6
Pages
e1001474
ISSN
  • 1549-1277 (ISSN-L)
  • 1549-1676
DOI
10.1371/journal.pmed.1001474
PMC
PMC3692470
OpenAlex
W2115060448
Cited by
203
References
51
Citations by year
2026: 5 · 2025: 8 · 2024: 6 · 2023: 8 · 2022: 9 · 2021: 15 · 2020: 14 · 2019: 21 · 2018: 17 · 2017: 23 · 2016: 30 · 2015: 22 · 2014: 20 · 2013: 5
FWCI
17.01
Type
journal article
Language
en
Open access
Licence
Locations
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Funders
  • Wellcome Trust (GR072960, 090532)
  • National Institute for Health and Care Research (NF-SI-0611-10099, SRF/01/010)
  • British Heart Foundation (PG/09/023/26806)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (184021007, 911-03-012, 918-76–619, 175.010.200)
  • Tartu Ülikool
  • Novo Nordisk Fonden (NNF12OC1016467)
  • National Institutes of Health (CT-2006-037593, CT-2006-019473, N01-RC- 45035, N01RC37004, n01rc37004-9-0-0, n01cn045165-030, 6r01hl087679-03, 5rl1mh083268-05, QLG2-CT-2002-01254, N01 RC037004, SF0180142S08, QLG1-CT-2000-0164)
  • Directorate for Biological Sciences
  • U.S. Public Health Service (230374, 911-03-012, 120315, 41795/1993, 10-000-1002, 904-61-090, R01D0042157‐01A, 141054, 129680, 11-0312, 104781, EU/QLRT-2001-01254, 201413, 911-09-032, 17155/2004, 01GS0834, A79801419, 904-61-193, 918-76-619, 480-04-004, EU/WLRT-2001-01254, 31737/1997, 56-464-14192, 139635, 31160008, ETF9353, 050-060-810, A7960034, 9783/1986, 213506, 129418, 129494, I 480-05-003, 400-05-717, A79906588, 985-10-002, CEED3 223211)
  • Medical Research Council
  • Biotechnology and Biological Sciences Research Council
  • Economic and Social Research Council (ES/G007438/1)
  • National Health and Medical Research Council (A7960034, A79906588, 389927, DP0212016, 241944, 339462, 389875, A79801419, DP0770096)
  • National Institute on Alcohol Abuse and Alcoholism (AA-10248, AA11998, K05AA017688, AA 15416, R01AA013321, P50AA011998, AA13320, AA13321, AA17688, R01AA013326, AA13326, R01AA013320, R01AA014041, R01AA015416, AA14041, R01AA007535, AA-07535)
  • National Institute on Aging (R01AG004563, AG-10175, AG04563, AG 08724, AG028555, R01AG028555, AG 08861, R01AG010175, R01AG008724)
  • National Heart, Lung, and Blood Institute (5R01 HL087679-02, R01 HL087679, R01HL089650)
  • National Institute of Mental Health (MH66206, R01MH059160, R01MH063706, RC2MH089995, RL1-MH083268, 1RL1MH083268-01, U24MH068457, 5R01MH63706, R01MH066206, RC2MH089951)
  • National Institute on Drug Abuse (R56DA012854, DA12854, R01DA012854)
  • National Eye Institute (R01EY018246, R01EY018246-01-1)
  • National Cancer Institute (N01 CN045165, N01 CN 45165)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01DK066134, DK U01‐066134)
  • National Center for Chronic Disease Prevention and Health Promotion (DP0212016, DP0343921, DP0770096)
  • FP7 Health (201413)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
Keywords
adiposity, body mass index, cardiometabolic traits, heart failure, type 2 diabetes, metabolic syndrome, dyslipidemia, hypertension, liver enzymes, alanine aminotransferase, gamma-glutamyl transferase, fasting insulin, C-reactive protein, triglycerides, HDL cholesterol, FTO, rs9939609, causal inference
MeSH terms
Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Cardiovascular Diseases, Humans, Proteins, Meta-Analysis as Topic, Confounding Factors, Epidemiologic, Body Mass Index, Case-Control Studies, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Adiposity, Genetic Association Studies, Mendelian Randomization Analysis

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