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Rare and common genetic determinants of metabolic individuality and their effects on human health.
Nat. Med. 28, 2321-2332 (2022)
Publ. Version/Full Text
Research data
DOI
PMC
Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Genome-wide Association; Inborn-errors; Variants; Disease; Identification; Deficiency; Prediction; Imputation; Database; Kidney
ISSN (print) / ISBN
1078-8956
e-ISSN
1546-170X
Journal
Nature medicine
Quellenangaben
Volume: 28,
Issue: 11,
Pages: 2321-2332
Publisher
Nature Publishing Group
Publishing Place
New York, NY
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Computational Biology (ICB)
Grants
German Federal Ministry of Education and Research
Cambridge Trust
Rutherford Fund Fellowship from the Medical Research Council
Wellcome
British Heart Foundation
Public Health Agency (Northern Ireland)
Health and Social Care Research and Development Division (Welsh Government)
Chief Scientist Office of the Scottish Government Health and Social Care Directorates
Department of Health and Social Care (England)
Economic and Social Research Council
Engineering and Physical Sciences Research Council
Health Data Research UK - UK Medical Research Council
UK Medical Research Council
NIHR Blood and Transplant Research Unit in Donor Health and Genomics
NIHR Cambridge BRC
Wellcome Trust
NIHR Cambridge Biomedical Research Centre
NIHR BioResource
National Institute for Health Research (NIHR)
Innovative Medicines Initiative Joint Undertaking under EMIF
MRC Cambridge Initiative in Metabolic Science
Cancer Research UK
Medical Research Council
QNRF
Qatar Foundation
Biomedical Research Program at Weill Cornell Medicine in Qatar
National Institute on Aging (NIA)
NIHR Senior Investigator Award
British Heart Foundation Professorship
BHF Accelerator Award
NIHR-UKRI CONVALESCENCE study
BHF Data Science Centre
Chronic Disease Research Foundation
BHF-Turing Cardiovascular Data Science Award
Innovative Medicines Initiative-2 Joint Undertaking
BHF Programme grant
National Institutes of Health
NIHR Birmingham Biomedical Research Centre
Wellcome Trust Investigator grant
BrightFocus Foundation
King's College London
Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
National Institute for Health Research (NIHR) Clinical Research Facility
European Commission H2020 grants SYSCID
NIHR Biomedical Research Centre at University College London (UCL) Hospital NHS Trust
Cambridge Trust
Rutherford Fund Fellowship from the Medical Research Council
Wellcome
British Heart Foundation
Public Health Agency (Northern Ireland)
Health and Social Care Research and Development Division (Welsh Government)
Chief Scientist Office of the Scottish Government Health and Social Care Directorates
Department of Health and Social Care (England)
Economic and Social Research Council
Engineering and Physical Sciences Research Council
Health Data Research UK - UK Medical Research Council
UK Medical Research Council
NIHR Blood and Transplant Research Unit in Donor Health and Genomics
NIHR Cambridge BRC
Wellcome Trust
NIHR Cambridge Biomedical Research Centre
NIHR BioResource
National Institute for Health Research (NIHR)
Innovative Medicines Initiative Joint Undertaking under EMIF
MRC Cambridge Initiative in Metabolic Science
Cancer Research UK
Medical Research Council
QNRF
Qatar Foundation
Biomedical Research Program at Weill Cornell Medicine in Qatar
National Institute on Aging (NIA)
NIHR Senior Investigator Award
British Heart Foundation Professorship
BHF Accelerator Award
NIHR-UKRI CONVALESCENCE study
BHF Data Science Centre
Chronic Disease Research Foundation
BHF-Turing Cardiovascular Data Science Award
Innovative Medicines Initiative-2 Joint Undertaking
BHF Programme grant
National Institutes of Health
NIHR Birmingham Biomedical Research Centre
Wellcome Trust Investigator grant
BrightFocus Foundation
King's College London
Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
National Institute for Health Research (NIHR) Clinical Research Facility
European Commission H2020 grants SYSCID
NIHR Biomedical Research Centre at University College London (UCL) Hospital NHS Trust