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A cross-platform approach identifies genetic regulators of human metabolism and health.

Accepted version
Peer-reviewed

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Type

Article

Change log

Authors

Lotta, Luca A 
Stewart, Isobel D 
Wittemans, Laura BL 
Li, Chen 

Abstract

In 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.

Description

Keywords

Diabetes Mellitus, Type 2, Eye Diseases, Gene Frequency, Genetic Loci, Genetic Pleiotropy, Genome, Human, Glucagon-Like Peptide-2 Receptor, Glycine, Health, Humans, Linear Models, Mendelian Randomization Analysis, Metabolism, Metabolism, Inborn Errors, Metabolome, Mutation, Missense, Phenotype, Polymorphism, Single Nucleotide, Retinal Telangiectasis, Sample Size, Serine

Journal Title

Nature Genetics

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

53

Publisher

Nature Research

Rights

All rights reserved
Sponsorship
Medical Research Council (MC_UU_12015/1)
Medical Research Council (MC_UU_12012/3)
Medical Research Council (MR/N003284/1)
Medical Research Council (MR/P011705/1)
Medical Research Council (MR/P01836X/1)
Medical Research Council (MR/S003746/1)
Medical Research Council (MC_PC_13030)
MRC (MC_UU_00006/1)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
Medical Research Council (G1000143)
Medical Research Council (G0500300)
Medical Research Council (G0401527)
Medical Research Council (MC_UU_00002/7)
MRC (MC_UU_00014/3)
MRC (MC_UU_00014/5)
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (CH/12/2/29428)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_PC_12012)