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The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis
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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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“IVs are widely used in econometric program evaluation and have attracted much recent interest in epidemiology, particularly in the context of Mendelian randomization studies, which use genetic variants as instruments for environmental exposures (25, 36, 48).”
From Natural Experiments: An Overview of Methods, Approaches, and Contributions to Public Health Intervention Research (2017) · cites this paper as [25]
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Mendelian randomization: A biologist's perspective
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Self-citationMabikwa, O. V. (2019) · White Rose eTheses Online (University of Leeds, The University of Sheffield, University of York)
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Martin, S., Tyrrell, J., Thomas, E. L., Bown, M. J., Wood, A. R., Beaumont, R. N., Tsoi, L. C., Stuart, P. E., Elder, J. T., Law, P., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-537397/v2
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Lind, L., & Zheng, R. (2025) · npj Cardiovascular Health · doi:10.1038/s44325-025-00073-7
Self-citationAdeyemo, A., Mogire, R. M., Chen, G., Doumatey, A. P., Meeks, K. A. C., Gouveia, M. H., Zhou, J., Bentley, A. R., Shriner, D., & Rotimi, C. N. (2025) · Research Square · doi:10.21203/rs.3.rs-6941679/v1 · Cited by 1
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Metadata
- 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
- Fall, Tove
- Hägg, Sara
- Mägi, Reedik
- Ploner, Alexander
- Fischer, Krista
- Horikoshi, Momoko
- Ladenvall, Claes
- Kals, Mart
- Draisma, Harmen H. M.
- 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
- Ikram, M. Arfan
- Amin, Najaf
- Braund, Peter S.
- Elliott, Paul
- Esko, Tõnu
- Franco, Oscar H.
- Herzig, Karl-Heinz
- Hottenga, Jouke Jan
- Hyppönen, Elina
- Isaacs, Aaron
- Karssen, Lennart C.
- Kettunen, Johannes
- Kuulasmaa, Kari
- Laatikainen, Tiina
- Laitinen, Jaana
- Lindgren, Cecilia
- Lyssenko, Valeriya
- Rayner, Nigel W.
- Männistö, Satu
- Pouta, Anneli
- Rathmann, Wolfgang
- Rivadeneira, Fernando
- Savolainen, Markku J.
- Sijbrands, Eric J. G.
- Small, Kerrin S.
- Tobin, Martin D.
- Willems, Sara M.
- Willemsen, Gonneke
- Perola, Markus
- Ferrières, Jean
- Kee, Frank
- Amouyel, Philippe
- Brambilla, Paolo
- Hall, Alistair S.
- Heath, Andrew C.
- Madden, Pamela A. F.
- Martin, Nicholas G.
- Montgomery, Grant W.
- Whitfield, John B.
- Knekt, Paul
- Penninx, Brenda W. J. H.
- Kaprio, Jaakko
- Samani, Nilesh J.
- Gieger, Christian
- Peters, Annette
- Wichmann, H.-Erich
- Boomsma, Dorret I.
- Power, Chris
- Hammond, Christopher J.
- Spector, Tim D.
- Lind, Lars
- Morris, Andrew D.
- Groop, Leif
- Järvelin, Marjo-Riitta
- Salomaa, Veikko
- Vartiainen, Erkki
- Ripatti, Samuli
- Metspalu, Andres
- Pedersen, Nancy L.
- McCarthy, Mark I.
- Ingelsson, Erik
- Prokopenko, Inga
- 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
- 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
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Research Portal (Queen's University Belfast) (publishedVersion, cc-by)
- VU Research Portal (publishedVersion, other-oa)
- Leicester Research Archive (University of Leicester) (acceptedVersion, other-oa)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- National University of Singapore (submittedVersion, cc-by)
- UniSA Research Outputs Repository (University of South Australia) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion, cc-by)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Työväentutkimus Vuosikirja (submittedVersion)
- IrInSubria (University of Insubria) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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