TY - JOUR
T1 - A phenome-wide comparative analysis of genetic discordance between obesity and type 2 diabetes
AU - Coral, Daniel E.
AU - Fernandez-Tajes, Juan
AU - Tsereteli, Neli
AU - Pomares-Millan, Hugo
AU - Fitipaldi, Hugo
AU - Mutie, Pascal M.
AU - Atabaki-Pasdar, Naeimeh
AU - Kalamajski, Sebastian
AU - Poveda, Alaitz
AU - Miller-Fleming, Tyne W.
AU - Zhong, Xue
AU - Giordano, Giuseppe N.
AU - Pearson, Ewan R.
AU - Cox, Nancy J.
AU - Franks, Paul W.
N1 - Funding Information:
This manuscript is part of the Stratification of Obesity Phenotypes to Optimize Future Therapy (SOPHIA) project. SOPHIA has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 875534. This Joint Undertaking support from the European Union’s Horizon 2020 research and innovation program and EFPIA and T1D Exchange, JDRF, and Obesity Action Coalition.This manuscript is part of the Stratification of Obesity Phenotypes to Optimize Future Therapy (SOPHIA) project. SOPHIA has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 875534. This Joint Undertaking is supported by the European Union’s Horizon 2020 research and innovation programme and EFPIA and T1D Exchange, JDRF and Obesity Action Coalition. NASCENT was funded by a grant from the European Commission (ERC-2015-CoG–681742 NASCENT). Additonal funding was provided by the Swedish Research Council (Distinguished Young Researcher Award) and the Swedish Foundation for Strategic Research (LUDC-IRC, 15-0067). All awards to PWF.
Copyright:
© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
PY - 2023/2
Y1 - 2023/2
N2 - Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical and molecular phenotypic layers. Key differences are identified in a wide range of traits, including cardiovascular mortality, fat distribution, liver metabolism, blood pressure, specific lipid fractions and blood levels of proteins involved in extracellular matrix remodelling. We find marginal differences in abundance of Bacteroidetes and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent causal roles for waist-to-hip ratio, blood pressure and cholesterol content of high-density lipoprotein particles in the development of diabetes in obesity. We prioritize 17 genes from the discordant signature that convey protection against type 2 diabetes in obesity, which may represent logical targets for precision medicine approaches.
AB - Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical and molecular phenotypic layers. Key differences are identified in a wide range of traits, including cardiovascular mortality, fat distribution, liver metabolism, blood pressure, specific lipid fractions and blood levels of proteins involved in extracellular matrix remodelling. We find marginal differences in abundance of Bacteroidetes and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent causal roles for waist-to-hip ratio, blood pressure and cholesterol content of high-density lipoprotein particles in the development of diabetes in obesity. We prioritize 17 genes from the discordant signature that convey protection against type 2 diabetes in obesity, which may represent logical targets for precision medicine approaches.
KW - Discordant diabesity
KW - Type 2 diabetes
KW - Genome-wide association studies
KW - Phenome-wide association studies
KW - Machine learning
KW - Genetic variation
KW - Metabolism
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=85146842321&partnerID=8YFLogxK
U2 - 10.1038/s42255-022-00731-5
DO - 10.1038/s42255-022-00731-5
M3 - Article
C2 - 36703017
SN - 2522-5812
VL - 5
SP - 237
EP - 247
JO - Nature Metabolism
JF - Nature Metabolism
ER -
