Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery
J German, Mattia Cordioli, Veronica Tozzo, Sarah Urbut, Kadri Arumäe, Roelof A. J. Smit, Jiwoo Lee, Josephine H. Li, Adrian Janucik, Yi Ding, Akintunde O. Akinkuolie, Henrike Heyne, Andrea Eoli, Chadi Saad, Yasser Al‐Sarraj, Rania G. Abdel‐latif, Shaban Mohammed, Moza Al Hail, Alexandra Barry, Zhe Wang, Tatiana Cajuso, Andrea Corbetta, Pradeep Natarajan, Samuli Ripatti, Anthony Philippakis, Łukasz Szczerbiński, Bogdan Paşaniuc, Zoltán Kutalik, Hamdi Mbarek, Ruth J. F. Loos, Uku Vainik, Andrea Ganna
Abstract
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.