
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.09.11.24313458
preprint
1
Article
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
German Jakob http://orcid.org/0009-0002-1257-7782

Cordioli Mattia http://orcid.org/0000-0002-4872-0520

Tozzo Veronica http://orcid.org/0000-0001-8538-9198

Urbut Sarah http://orcid.org/0000-0002-1135-9647

Arumäe Kadri http://orcid.org/0000-0001-9950-904X

Smit Roelof A.J. http://orcid.org/0000-0001-9822-6726

Lee Jiwoo http://orcid.org/0000-0003-0555-585X

Li Josephine H. http://orcid.org/0000-0003-2314-0914

Janucik Adrian
Ding Yi
Akinkuolie Akintunde
Heyne Henrike
Eoli Andrea http://orcid.org/0000-0002-6505-3117

Saad Chadi
Al-Sarraj Yasser
Abdel-latif Rania
Barry Alexandra
Wang Zhe http://orcid.org/0000-0002-8046-4969

Estonian Biobank research team
Natarajan Pradeep http://orcid.org/0000-0001-8402-7435

Ripatti Samuli
Philippakis Anthony
Szczerbinski Lukasz http://orcid.org/0000-0002-6201-0605

Pasaniuc Bogdan
Mbarek Hamdi http://orcid.org/0000-0002-1108-0371

Loos Ruth J.F. http://orcid.org/0000-0002-8532-5087

Vainik Uku http://orcid.org/0000-0002-9375-9520

Ganna Andrea
12 9 2024
2024.09.11.24313458https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.09.11.24313458
nihpp-2024.09.11.24313458.pdf
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. However, 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 ). In contrast, higher weight at baseline was associated with greater weight loss. 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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