Lotta, Luca A.Pietzner, MaikStewart, Isobel D.Wittemans, Laura B. L.Li, ChenBonelli, RobertoRaffler, JohannesBiggs, Emma K.Oliver-Williams, ClareAuyeung, Victoria P. W.Paige, Ellie2024-02-231061-4036http://hdl.handle.net/1885/313837In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10−10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.M.P. was supported by a fellowship from the German Research Foundation (DFG PI 1446/2-1). C.O.-W. was funded by an early career fellowship at Homerton College, University of Cambridge. L.B.L.W. acknowledges funding from the Wellcome Trust (WT083442AIA). J.L.G. was supported by grants from the Medical Research Council (MC_UP_A090_1006, MC_PC_13030, MR/P011705/1 and MR/P01836X/1). Work in the Reimann and Gribble laboratories was supported by the Wellcome Trust (106262/Z/14/Z and 106263/Z/14/Z), the UK Medical Research Council (MRC_MC_ UU_12012/3) and PhD funding for E.K.B. from MedImmune/AstraZeneca. P.S. is supported by a Rutherford Fund Fellowship from the Medical Research Council (MR/ S003746/1). A.M.W. is supported by a BHF-Turing Cardiovascular Data Science Award and by the EC-Innovative Medicines Initiative (BigData@Heart). J.R. is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of e:Med research and funding concept (grant no. 01ZX1912D). J.D. is funded by the National Institute for Health Research (NIHR; Senior Investigator Award) (*). The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). The genetic work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372. The Fenland study is supported by the UK Medical Research Council (MC_UU_12015/1 and MC_PC_13046). Nightingale Health NMR assays were funded by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). Metabolon Metabolomics assays, the academic coordinating center, DNA extraction and genotyping for INTERVAL were supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (SP/09/002, RG/13/13/30194 and RG/18/13/33946), the NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust) and the NIHR BioResource (http://bioresource.nihr.ac.uk) (*). This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the British Heart Foundation and Wellcome. We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who enabled this research. *The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. UK Biobank: this research was conducted using the UK Biobank resource under application no. 44448.application/pdfen-AU© 2021 Nature Publishing GroupA cross-platform approach identifies genetic regulators of human metabolism and health202110.1038/s41588-020-00751-52022-10-09