Rare variants of the glucagon-like peptide-1 receptor (GLP1R) gene are overrepresented in a severe obesity cohort and associated with type 2 diabetes in the UK Biobank

Introduction: Glucagon-like peptide 1 (GLP1) agonists are highly effective agents for the treatment of obesity and type 2 diabetes (T2D). GLP-1 is also implicated in outcomes of bariatric surgery, including appetite changes and T2D remission. Rare, potentially deleterious mutations in the glucagon-like peptide 1 receptor gene (GLP1R) may, therefore, have important implications for pathogenesis of obesity and T2D, and for response to therapeutic interventions. Methods: A custom Axion genotyping array, including 117 rare predicted-deleterious GLP1R mutations (MAF<0.01 in gnomAD, CADD-PHRED >= 15), was used to screen 1714 unrelated adults with BMI >35 kg/m2 from the PMMO study. We also examined the UK Biobank (UKB) exome sequence dataset for rare, predicted-deleterious GLP1R variants and tested their effects on weight and glycaemia-related traits. Results: Thirty-four PMMO participants carried one of the 117 GLP1R variants screened (11 might have been expected using the sum of their gnomAD control MAFs). These 8 variants were associated with T2D in the UKB and subsequent gene-level analysis of the UKB exome sequence dataset (629/39,274 carriers) confirmed that rare GLP1R variants are associated with increased risk of T2D (OR=1.58), as well as with higher HbA1c levels (p= 0.039). Furthermore, our data highlight a potential interaction of these variants with body mass index. Conclusion: Rare, potentially deleterious GLP1R mutations is associated with increased T2D risk, as well as higher HbA1c in UKB participants without diabetes. Future studies should examine the implications of GLP1R mutations for response to GLP1 agonist treatment and explore the observed interactions with obesity in T2D risk, including in larger cohorts with obesity. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was funded by Brunel University London. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of Brunel University London gave ethical approval for this work. Ethics Committee of NRES Committee London Riverside, NHS gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.