Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities

Nathalie Chami^#^{1

2

3}, Zhe Wang^#^{1

2

4}, Victor Svenstrup^{3

5}, Virginia Diez Obrero^{3

5}, Daiane Hemerich^{1

6}, Yi Huang^{3

7}, Hesam Dashti^{3

7

8}, Eleonora Manitta^{3

5}, Michael H Preuss¹, Kari E North⁹, Louise Aas Holm⁵, Cilius E Fonvig^{5

10}, Jens-Christian Holm^{5

10}, Torben Hansen⁵, Camilla Scheele^{3

5}, Alexander Rauch^{11

12

13}, Roelof A J Smit^{1

3

5}, Melina Claussnitzer^{3

7

8}, Ruth J F Loos^{14

15

16

17}

Affiliations

¹ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
⁵ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶ Bristol Myers Squibb, Princeton, NJ, USA.
⁷ Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Center for Genomic Medicine and Endocrine Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ The Children's Obesity Clinic, accredited European Centre for Obesity Management, Department of Paediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark.
¹¹ Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹² Molecular Endocrinology & Stem Cell Research Unit, Department of Endocrinology, Odense University Hospital, Odense, Denmark.
¹³ Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark.
¹⁴ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ruth.loos@sund.ku.dk.
¹⁵ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ruth.loos@sund.ku.dk.
¹⁶ The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ruth.loos@sund.ku.dk.
¹⁷ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. ruth.loos@sund.ku.dk.

^# Contributed equally.

PMID: 40940440
DOI: 10.1038/s41591-025-03931-0

Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities

Nathalie Chami et al. Nat Med. 2025.

. 2025 Sep 12.

doi: 10.1038/s41591-025-03931-0. Online ahead of print.

Authors

Affiliations

¹ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
⁵ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶ Bristol Myers Squibb, Princeton, NJ, USA.
⁷ Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Center for Genomic Medicine and Endocrine Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ The Children's Obesity Clinic, accredited European Centre for Obesity Management, Department of Paediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark.
¹¹ Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹² Molecular Endocrinology & Stem Cell Research Unit, Department of Endocrinology, Odense University Hospital, Odense, Denmark.
¹³ Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark.
¹⁴ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ruth.loos@sund.ku.dk.
¹⁵ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ruth.loos@sund.ku.dk.
¹⁶ The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA. ruth.loos@sund.ku.dk.
¹⁷ The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. ruth.loos@sund.ku.dk.

^# Contributed equally.

PMID: 40940440
DOI: 10.1038/s41591-025-03931-0

Abstract

Obesity is a heterogeneous condition not adequately captured by a single adiposity trait. We conducted a multi-trait genome-wide association analysis using individual-level data from 452,768 UK Biobank participants to study obesity in relation to cardiometabolic health. We defined continuous 'uncoupling phenotypes', ranging from high adiposity with healthy cardiometabolic profiles to low adiposity with unhealthy ones. We identified 266 variants across 205 genomic loci where adiposity-increasing alleles were simultaneously associated with lower cardiometabolic risk. A genetic risk score (GRS_uncoupling) aggregating these variants was associated with a lower risk of cardiometabolic disorders, including dyslipidemia and ischemic heart disease, despite higher obesity risk; unlike an adiposity score based on body fat percentage-associated variants (GRS_BFP). The 266 variants formed eight genetic subtypes of obesity, each with distinct risk profiles and pathway signatures. Proteomic analyses revealed signatures separating adiposity- and health-driven effects. Our findings reveal new mechanisms that uncouple obesity from cardiometabolic comorbidities and lay a foundation for genetically informed subtyping of obesity to support precision medicine.

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Conflict of interest statement

Competing interests: J.C.H. has received honoraria for expert roles from Novo Nordisk and Rhythm Pharmaceuticals and provides training and treatment of obesity. All the other authors declare no competing interests.

Update of

Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities.
Chami N, Wang Z, Svenstrup V, Diez Obrero V, Hemerich D, Huang Y, Dashti H, Manitta E, Preuss MH, North KE, Holm LA, Fonvig CE, Holm JC, Hansen T, Scheele C, Rauch A, Smit RAJ, Claussnitzer M, Loos RJF. Chami N, et al. medRxiv [Preprint]. 2025 Feb 28:2025.02.25.25322830. doi: 10.1101/2025.02.25.25322830. medRxiv. 2025. Update in: Nat Med. 2025 Sep 12. doi: 10.1038/s41591-025-03931-0. PMID: 40061343 Free PMC article. Updated. Preprint.

References

1. Mokdad, A. H. et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289, 76–79 (2003). - PubMed - DOI
1. Alberti, K. G. et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120, 1640–1645 (2009). - PubMed - DOI
1. Hubert, H. B., Feinleib, M., McNamara, P. M. & Castelli, W. P. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 67, 968–977 (1983). - PubMed - DOI
1. Must, A. et al. The disease burden associated with overweight and obesity. JAMA 282, 1523–1529 (1999). - PubMed - DOI
1. Loos, R. J. F. & Yeo, G. S. H. The genetics of obesity: from discovery to biology. Nat. Rev. Genet. 23, 120–133 (2022). - PubMed - DOI

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Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities

Affiliations

Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources