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  Composite trait Mendelian randomization reveals distinct metabolic and lifestyle consequences of differences in body shape

Sulc, J., Sonrel, A., Mounier, N., Auwerx, C., Marouli, E., Darrous, L., et al. (2021). Composite trait Mendelian randomization reveals distinct metabolic and lifestyle consequences of differences in body shape. Communications Biology, 4: 1064. doi:10.1038/s42003-021-02550-y.

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 Creators:
Sulc, Jonathan1, 2, Author
Sonrel, Anthony2, 3, Author
Mounier, Ninon1, 2, Author
Auwerx, Chiara1, 2, 4, Author
Marouli, Eirini5, 6, Author
Darrous, Liza1, 2, Author
Draganski, Bogdan7, 8, Author              
Kilpeläinen, Tuomas O.9, Author
Joshi, Peter10, Author
Loos, Ruth J. F.11, 12, 13, Author
Kutalik, Zoltán1, 2, 14, Author
Affiliations:
1Center for Primary Care and Public Health, University of Lausanne, Switzerland, ou_persistent22              
2Swiss Institute of Bioinformatics, University of Lausanne, Switzerland, ou_persistent22              
3Department of Molecular Life Sciences, University of Zurich, Switzerland, ou_persistent22              
4Center for Integrative Genomics, University of Lausanne, Switzerland, ou_persistent22              
5William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom, ou_persistent22              
6Centre for Genomic Health, Queen Mary University of London, United Kingdom, ou_persistent22              
7Département des Neurosciences Cliniques, Laboratoire de Recherche en Neuroimagerie (LREN), Centre hospitalier universitaire vaudois, Lausanne, Switzerland, ou_persistent22              
8Department Neurology, MPI for Human Cognitive and Brain Sciences, Max Planck Society, ou_634549              
9Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, ou_persistent22              
10Usher Institute, University of Edinburgh, United Kingdom, ou_persistent22              
11Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA, ou_persistent22              
12Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA, ou_persistent22              
13Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA, ou_persistent22              
14Genetics of Complex Traits, Medical School, University of Exeter, United Kingdom, ou_persistent22              

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Free keywords: Obesity; Risk factors
 Abstract: Obesity is a major risk factor for a wide range of cardiometabolic diseases, however the impact of specific aspects of body morphology remains poorly understood. We combined the GWAS summary statistics of fourteen anthropometric traits from UK Biobank through principal component analysis to reveal four major independent axes: body size, adiposity, predisposition to abdominal fat deposition, and lean mass. Mendelian randomization analysis showed that although body size and adiposity both contribute to the consequences of BMI, many of their effects are distinct, such as body size increasing the risk of cardiac arrhythmia (b = 0.06, p = 4.2 ∗ 10-17) while adiposity instead increased that of ischemic heart disease (b = 0.079, p = 8.2 ∗ 10-21). The body mass-neutral component predisposing to abdominal fat deposition, likely reflecting a shift from subcutaneous to visceral fat, exhibited health effects that were weaker but specifically linked to lipotoxicity, such as ischemic heart disease (b = 0.067, p = 9.4 ∗ 10-14) and diabetes (b = 0.082, p = 5.9 ∗ 10-19). Combining their independent predicted effects significantly improved the prediction of obesity-related diseases (p < 10-10). The presented decomposition approach sheds light on the biological mechanisms underlying the heterogeneity of body morphology and its consequences on health and lifestyle.

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 Dates: 2021-06-032021-08-122021-09-13
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/s42003-021-02550-y
PMID: 34518635
PMC: PMC8438050
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Project name : -
Grant ID : 31003A-143914, 310030-189147, 32003B_135679, 32003B_159780, 324730_192755, and CRSK-3_190185
Funding program : -
Funding organization : Swiss National Science Foundation
Project name : -
Grant ID : NNF17OC0026848, NNF18CC0034900
Funding program : -
Funding organization : Novo Nordisk Foundation

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Title: Communications Biology
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: - Volume / Issue: 4 Sequence Number: 1064 Start / End Page: - Identifier: ISSN: 2399-3642
CoNE: https://pure.mpg.de/cone/journals/resource/2399-3642