Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery

Jakob German; Mattia Cordioli; Veronica Tozzo; Sarah Urbut; Kadri Arumäe; Roelof A J Smit; Jiwoo Lee; Josephine H Li; Adrian Janucik; Yi Ding; Akintunde Akinkuolie; Henrike O Heyne; Andrea Eoli; Chadi Saad; Yasser Al-Sarraj; Rania Abdel-Latif; Shaban Mohammed; Moza Al Hail; Alexandra Barry; Zhe Wang; Tatiana Cajuso; Andrea Corbetta; Pradeep Natarajan; Samuli Ripatti; Anthony Philippakis; Lukasz Szczerbinski; Bogdan Pasaniuc; Zoltán Kutalik; Hamdi Mbarek; Ruth J F Loos; Uku Vainik; Andrea Ganna

doi:10.1038/s41591-025-03645-3

Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery

Nat Med. 2025 Apr 18. doi: 10.1038/s41591-025-03645-3. Online ahead of print.

Authors

Jakob German^#^{1

2}, Mattia Cordioli^#^{1

3}, Veronica Tozzo⁴, Sarah Urbut^{5

6

7}, Kadri Arumäe⁸, Roelof A J Smit^{9

10

11

12}, Jiwoo Lee^{3

6}, Josephine H Li^{6

13

14

15}, Adrian Janucik^{14

16}, Yi Ding⁴, Akintunde Akinkuolie⁴, Henrike O Heyne^{17

18}, Andrea Eoli¹⁸, Chadi Saad¹⁹, Yasser Al-Sarraj¹⁹, Rania Abdel-Latif¹⁹, Shaban Mohammed²⁰, Moza Al Hail²⁰, Alexandra Barry^{6

14

21}, Zhe Wang^{9

22}, Tatiana Cajuso^{1

23}, Andrea Corbetta^{1

24

25}, Pradeep Natarajan^{6

14

26

27}, Samuli Ripatti^{1

14

28

29}, Anthony Philippakis^{2

3}, Lukasz Szczerbinski^{6

13

30

31

32}, Bogdan Pasaniuc^{4

33

34

35

36}, Zoltán Kutalik^{37

38

39}, Hamdi Mbarek¹⁹, Ruth J F Loos^{9

10

11

12}, Uku Vainik^{8

40

41}, Andrea Ganna^{42

43}

Affiliations

¹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
² Eric and Wendy Schmidt Center, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Computational Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁵ Division of Cardiovascular Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
⁸ Institute of Psychology, University of Tartu, Tartu, Estonia.
⁹ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
¹² Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Program in Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁵ Harvard Medical School, Boston, MA, USA.
¹⁶ Center for Digital Medicine, Medical University of Bialystok, Bialystok, Poland.
¹⁷ Hasso Plattner Institute, University of Potsdam, Potsdam, Germany.
¹⁸ Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Qatar Genome Program, Qatar Precision Health Institute, Qatar Foundation, Doha, Qatar.
²⁰ Department of Pharmacy, Hamad Medical Corporation, Doha, Qatar.
²¹ Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²² Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
²³ Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
²⁴ Health Data Science Centre, Human Technopole, Milan, Italy.
²⁵ MOX - Laboratory for Modeling and Scientific Computing, Department of Mathematics, Politecnico di Milano, Milan, Italy.
²⁶ Personalized Medicine, Mass General Brigham, Boston, MA, USA.
²⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁸ Department of Public Health, Clinicum, University of Helsinki, Helsinki, Finland.
²⁹ Analytic & Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³⁰ Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³¹ Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.
³² Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland.
³³ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, USA.
³⁴ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
³⁵ Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
³⁶ Institute of Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁷ University Center for Primary Care and Public Health, Lausanne, Switzerland.
³⁸ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
³⁹ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁴⁰ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁴¹ Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
⁴² Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. andrea.ganna@helsinki.fi.
⁴³ Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. andrea.ganna@helsinki.fi.

^# Contributed equally.

PMID: 40251273
DOI: 10.1038/s41591-025-03645-3

Abstract

Obesity is a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP1-RA) and bariatric surgery (BS) are effective weight loss interventions; however, the genetic factors influencing treatment response remain largely unexplored. Moreover, most previous studies have focused on race and ethnicity rather than genetic ancestry. Here we analyzed 10,960 individuals from 9 multiancestry biobank studies across 6 countries to assess the impact of known genetic factors on weight loss. Between 6 and 12 months, GLP1-RA users had an average weight change of -3.93% or -6.00%, depending on the outcome definition, with modest ancestry-based differences. BS patients experienced -21.17% weight change between 6 and 48 months. We found no significant associations between GLP1-RA-induced weight loss and polygenic scores for body mass index or type 2 diabetes, nor with missense variants in GLP1R. A higher body mass index polygenic score was modestly linked to lower weight loss after BS (+0.7% per s.d., P = 1.24 × 10^-4), but the effect attenuated in sensitivity analyses. Our findings suggest known genetic factors have limited impact on GLP1-RA effectiveness with respect to weight change and confirm treatment efficacy across ancestry groups.

Abstract

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