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[Preprint]. 2025 Jan 8:2024.09.11.24313458.

doi: 10.1101/2024.09.11.24313458.

Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery: a multi-ancestry study in 10 960 individuals from 9 biobanks

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 Heyne¹⁷, Andrea Eoli^{18

19}, Chadi Saad²⁰, Yasser Al-Sarraj²⁰, Rania Abdel-Latif²⁰, Shaban Mohammed²¹, Moza Al Hail²¹, Alexandra Barry^{6

14}, Zhe Wang⁹; Estonian Biobank research team; Tatiana Cajuso^{1

22}, Andrea Corbetta^{1

23

24}, Pradeep Natarajan^{6

14

25

26}, Samuli Ripatti^{1

14

27

28}, Anthony Philippakis^{2

3}, Lukasz Szczerbinski^{6

13

29

30

31}, Bogdan Pasaniuc^{4

32

33

34

35}, Zoltan Kutalik^{36

37

38}, Hamdi Mbarek²⁰, Ruth J F Loos^{9

10

11

12}, Uku Vainik^{8

39

40}, Andrea Ganna^{1

28}

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, 02142.
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.
⁶ Center for Genomic Medicine Massachusetts General Hospital, Boston, MA.
⁷ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA.
⁸ Institute of Psychology, Faculty of Social Sciences, University of Tartu, Tartu, Estonia.
⁹ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, 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 Institut, Potsdam, Germany.
¹⁸ Digital Engineering Faculty, University of Potsdam, Potsdam, Germany, Prof.-Dr.-Helmert-Str. 2-3, 14482.
¹⁹ Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
²⁰ Qatar Genome Program, Qatar Precision Health Institute, Qatar Foundation, Doha, Qatar.
²¹ Department of Pharmacy, Hamad Medical Corporation, Doha, Qatar.
²² Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA.
²³ Health Data Science Centre, Human Technopole, Milan, Italy.
²⁴ MOX - Laboratory for Modeling and Scientific Computing, Department of Mathematics, Politecnico di Milano, Milan,Italy.
²⁵ Personalized Medicine, Mass General Brigham, Boston, MA, USA.
²⁶ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁷ Department of Public Health, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²⁸ Analytic & Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁹ Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁰ Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.
³¹ Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland.
³² Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA.
³³ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
³⁴ Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
³⁵ Institute for Precision Health, UCLA, Los Angeles, CA, USA.
³⁶ University Center for Primary Care and Public Health, Lausanne, Switzerland.
³⁷ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
³⁸ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
³⁹ Estonian Genome Centre, Institute of Genomics, Faculty of Science and Technology, University of Tartu, Tartu, Estonia.
⁴⁰ Department of Neurology and Neurosurgery, Faculty of Medicine and Health Sciences, McGill University, Canada.

PMID: 39314946
PMCID: PMC11419199
DOI: 10.1101/2024.09.11.24313458

Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery: a multi-ancestry study in 10 960 individuals from 9 biobanks

Jakob German et al. medRxiv. 2025.

[Preprint]. 2025 Jan 8:2024.09.11.24313458.

doi: 10.1101/2024.09.11.24313458.

Authors

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, 02142.
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.
⁶ Center for Genomic Medicine Massachusetts General Hospital, Boston, MA.
⁷ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA.
⁸ Institute of Psychology, Faculty of Social Sciences, University of Tartu, Tartu, Estonia.
⁹ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Department of Environmental Medicine and Climate Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, 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 Institut, Potsdam, Germany.
¹⁸ Digital Engineering Faculty, University of Potsdam, Potsdam, Germany, Prof.-Dr.-Helmert-Str. 2-3, 14482.
¹⁹ Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
²⁰ Qatar Genome Program, Qatar Precision Health Institute, Qatar Foundation, Doha, Qatar.
²¹ Department of Pharmacy, Hamad Medical Corporation, Doha, Qatar.
²² Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115, USA.
²³ Health Data Science Centre, Human Technopole, Milan, Italy.
²⁴ MOX - Laboratory for Modeling and Scientific Computing, Department of Mathematics, Politecnico di Milano, Milan,Italy.
²⁵ Personalized Medicine, Mass General Brigham, Boston, MA, USA.
²⁶ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁷ Department of Public Health, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
²⁸ Analytic & Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁹ Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³⁰ Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.
³¹ Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland.
³² Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA.
³³ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
³⁴ Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
³⁵ Institute for Precision Health, UCLA, Los Angeles, CA, USA.
³⁶ University Center for Primary Care and Public Health, Lausanne, Switzerland.
³⁷ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
³⁸ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
³⁹ Estonian Genome Centre, Institute of Genomics, Faculty of Science and Technology, University of Tartu, Tartu, Estonia.
⁴⁰ Department of Neurology and Neurosurgery, Faculty of Medicine and Health Sciences, McGill University, Canada.

PMID: 39314946
PMCID: PMC11419199
DOI: 10.1101/2024.09.11.24313458

Update in

Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery.
German J, Cordioli M, Tozzo V, Urbut S, Arumäe K, Smit RAJ, Lee J, Li JH, Janucik A, Ding Y, Akinkuolie A, Heyne HO, Eoli A, Saad C, Al-Sarraj Y, Abdel-Latif R, Mohammed S, Hail MA, Barry A, Wang Z, Cajuso T, Corbetta A, Natarajan P, Ripatti S, Philippakis A, Szczerbinski L, Pasaniuc B, Kutalik Z, Mbarek H, Loos RJF, Vainik U, Ganna A. German J, et al. Nat Med. 2025 Jul;31(7):2269-2276. doi: 10.1038/s41591-025-03645-3. Epub 2025 Apr 18. Nat Med. 2025. PMID: 40251273 Free PMC article.

Abstract

Obesity is a significant public health concern. GLP-1 receptor agonists (GLP1-RA), predominantly in use as a type 2 diabetes treatment, are a promising pharmacological approach for weight loss, while bariatric surgery (BS) remains a durable, but invasive, intervention. Despite observed heterogeneity in weight loss effects, the genetic effects on weight loss from GLP1-RA and BS have not been extensively explored in large sample sizes, and most studies have focused on differences in race and ethnicity, rather than genetic ancestry. We studied whether genetic factors, previously shown to affect body weight, impact weight loss due to GLP1-RA therapy or BS in 10,960 individuals from 9 multi-ancestry biobank studies in 6 countries. The average weight change between 6 and 12 months from therapy initiation was -3.93% for GLP1-RA users, with marginal differences across genetic ancestries. For BS patients the weight change between 6 and 48 months from the operation was -21.17%. There were no significant associations between weight loss due to GLP1-RA and polygenic scores for BMI or type 2 diabetes or specific missense variants in the GLP1R, PCSK1 and APOE genes, after multiple-testing correction. A higher polygenic score for BMI was significantly linked to lower weight loss after BS (+0.7% for 1 standard deviation change in the polygenic score, P = 1.24×10^-4), but the effect was modest and further reduced in sensitivity analyses. Our findings suggest that existing polygenic scores related to weight and type 2 diabetes and missense variants in the drug target gene do not have a large impact on GLP1-RA effectiveness. Our results also confirm the effectiveness of these treatments across all major continental ancestry groups considered.

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Figures

**Figure 1 |. Average percentage change in body weight for 6 750 GLP1-RA users and 4 210 bariatric surgery patients.**
Bars represent the mean percentage change in body weight within each study and ancestry, and the overall combined weighted mean change. Error bars represent standard errors.

**Figure 2 |. Effect of 15 genetic exposures on body weight changes associated with GLP1-RA treatment and bariatric surgery.**
a. Ancestry-specific and multi-ancestry meta-analysis effect sizes for association between percentage change in body weight and PGS for BMI and type 2 diabetes. Dots represent the percentage change in body weight per one standard deviation change in PGS, error bars represent the 95% confidence interval. Full dots represent statistical significance at P < 0.004. b. Multi-ancestry meta-analysis effect sizes for the association between percentage change in body weight and genotype at each locus. Dots represent the effect size, error bars represent the 95% confidence interval. PGS, polygenic score.

See this image and copyright information in PMC

References

1. Hruby A. & Hu F. B. The Epidemiology of Obesity: A Big Picture. Pharmacoeconomics 33, 673–689 (2015). - PMC - PubMed
1. Boutari C. & Mantzoros C. S. A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on. Metabolism 133, 155217 (2022). - PMC - PubMed
1. EASO Secretariat. European survey finds over three-quarters of adults with obesity have attempted to lose weight in the past year, but most have been unsuccessful. EASO https://easo.org/european-survey-finds-over-three-quarters-of-adults-wit... (2022).
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This is a preprint.

Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery: a multi-ancestry study in 10 960 individuals from 9 biobanks

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Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery: a multi-ancestry study in 10 960 individuals from 9 biobanks

Authors

Affiliations

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Abstract

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