Association of genetic variants with metabolic traits and multiple disease outcomes to inform therapeutic target validation: strengths and limitations of a GLP1R variant. D. F. Freitag1,2, R. A. Scott3, L. Li4, J. L. Aponte5, S. M. Willems6, J. Wessel7,8, A. Y. Chu9, S. Wang10, P. Munroe11, M. den Hoed12, I. B. Borecki13, C. Liu14, G. M. Peloso15,16,17, J. M. M. Howson1, A. S. Butterworth1, J. Danesh1,2, J. Dupuis10, J. I. Rotter18, J. B. Meigs19,20, M. O. Goodarzi21, S. O'Rahilly22, M. G. Ehm4, N. J. Wareham3, D. Waterworth23, CVD50 consortium, CHARGE Consortium,The CHD Exome+ Consortium, CARDIOGRAM Exome 1) Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; 2) The Wellcome Trust Sanger Institute, Hinxton, UK; 3) MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK; 4) Statistical Genetics, PCPS, GlaxoSmithKline, RTP, NC, USA; 5) Genetics, PCPS, GlaxoSmithKline, RTP, NC, USA; 6) Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; 7) Fairbanks School of Public Health, Department of Epidemiology, Indianapolis, IN, USA; 8) Indiana University School of Medicine, Department of Medicine, Indianapolis, IN, USA; 9) Division of Preventive Medicine, Brigham and Women's Hospital, Boston MA, USA; 10) Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; 11) Clinical Pharmacology, William Harvey Research Institute, Barts and The London, Queen Mary University of London, London, UK; 12) Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; 13) Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine. St. Louis, MO, USA; 14) Framingham Heart Study, Population Sciences Branch, NHLBI/NIH, Bethesda, MD, USA; 15) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; 16) Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA; 17) Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; 18) Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA; 19) Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; 20) Department of Medicine, Harvard Medical School, Boston, MA, USA; 21) Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 22) University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrookes Hospital, Cambridge, UK; 23) Genetics, PCPS, GlaxoSmithKline, Philadelphia, PA, USA.

   We investigated the association of genetic variants in 202 genes encoding drug targets with a range of type 2 diabetes (T2D) and obesity-related traits in three studies comprising up to 11,806 individuals with exome sequencing. We sought to identify genetic variants showing promising on-target associations with these traits, which may then inform the safety profile or alternative indications for drugs being developed or marketed for obesity and/or T2D. We identified associations in seven genes encoding relevant targets which we took forward for replication by targeted genotyping in five additional studies comprising up to 39,979 participants of European ancestry, and by in silico replication for SNPs where available. Following replication, we identified a low frequency (~1% MAF) missense variant (Ala316Thr; rs10305492) in the GLP1R gene (encoding the target of the GLP1R-agonist class of T2D-therapies) associated with fasting glucose ( in SDs per (minor) A allele [95% CI]=-0.14 [-0.19, -0.09]; p=1.1x10-8; n=39,753). The minor allele at this variant was also associated with lower risk of T2D (Odds Ratio (OR) =0.83 [0.76, 0.91]; p=9.4x10-5; ncases=25,868, ncontrols=122,393). We then performed a comprehensive assessment of the association of the GLP1R variant with a range of phenotypes, comparing them to results observed in clinical trials of GLP1R agonists. While we observed that, similar to GLP1R-agonist therapy, the minor allele was associated with lower fasting glucose and lower risk of T2D, it was not associated with 2-h glucose ( in SDs =0.07 [-0.02, 0.16]; p=0.15; n=39,600), with an opposite direction of effect to that observed in clinical trials. We investigated the association of the variant with other disease outcomes and observed an association of the minor allele with lower risk of coronary heart disease (CHD) (OR)=0.93 [0.87-0.98]; p=0.009; ncases=61,846, ncontrols=163,728). However, we found no evidence of a significant association of this variant with pancreatic cancer (OR = 1.23 [0.77, 1.97]; p=0.39; ncases=2,307, ncontrols=2,333), with the wide confidence interval indicating the need for far larger sample sizes to inform the safety profile. We demonstrate the potential in using genetic variants with on-target associations to predict downstream or off-target effects, whilst highlighting some of the challenges of this approach, including the scale of international collaboration required to realise this potential.

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