Identification and characterization of human GDF15 knockouts

Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight, and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans caused nausea without accompanying weight loss2, and the effect of GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3-7. Here, we characterize GDF15 loss-of-function carriers (LOF), including 5 homozygous null carriers (knockouts) from 75,018 participants enrolled in the Pakistan Genomic Resource (PGR)8,9. We tested for the association of GDF15 LOF with 97 quantitative traits and binary outcomes. Further, 3 additional knockouts and 59 heterozygous carriers were identified in recall-by-genotype (RBG) studies accompanied by recruitment of family members. GDF15 knockouts ranged in age from 31 to 75 years, were fertile, and showed no consistent overt metabolic dysfunction. Collectively, our data indicate that: (i) complete GDF15 loss is compatible with life and fertility, (ii) chronic therapeutic inhibition of GDF15 may be tolerated, and (iii) GDF15 modulation may not significantly impact body weight or metabolic syndrome. ### Competing Interest Statement D.S. has received funding from Regeneron Pharmaceuticals, Eli Lilly & Company, Novartis, Merck, Astra Zeneca, NGM Biopharmaceuticals Inc., GSK, Astellas Pharma Inc., and Novo Nordisk. Sequencing for 37,804 exomes was performed at the Regeneron Genetics Center, Tarrytown, New York. A.M.G., C.K., L.B.L., E.D., A.M.C., R.Z., M.E.C., Z.C, L.D.L, Y.H.C., R.S.S., D.P.D., A.B.G., and J.E.D. are employees of Novartis. B.D. is an employee of Tango Therapeutics. A.A. and J.L.H. are employees of AstraZeneca. K.T., M.A., and I.K. are employees of Astellas Pharma. A.R.S. and J.L.R. are employees of the Regeneron Genetics Center. ### Funding Statement Part of this work has been funded by the National Institutes of Health (NIH). Industry-affiliated authors were funded by their respective employers, as listed in the "Competing Interests" statement. The Center for Non-Communicable Diseases (CNCD) received funding from the Regeneron Genetics Center, AstraZeneca, Astellas, and Novartis for work reported in this study. ### 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: The Institutional Review Board (IRB) at the Center for Non-Communicable Diseases (IRB: 00007048, IORG0005843, FWAS00014490) gave ethical approval for this work. The National Bioethics Committee for Research Pakistan (Reference number: NBC-756) gave ethical approval for this work. All participants gave written informed consent. 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 academic requests to access relevant data should be sent to ks76@cncdpk.com. CNCD will ask relevant investigators to sign a data confidentiality agreement which would limit any investigator not to de-identify any of the study participants.