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Surendran, P.* ; Stewart, I.D.* ; Au Yeung, V.P.W.* ; Pietzner, M.* ; Raffler, J. ; Wörheide, M. ; Li, C.* ; Smith, R.F.* ; Wittemans, L.B.L.* ; Bomba, L.* ; Menni, C.* ; Zierer, J.* ; Rossi, N.* ; Sheridan, P.A.* ; Watkins, N.A.* ; Mangino, M.* ; Hysi, P.G.* ; Falchi, M.* ; Spector, T.D.* ; Michelotti, G.A.* ; Arlt, W.* ; Lotta, L.A.* ; Denaxas, S.* ; Hemingway, H.* ; Gamazon, E.R.* ; Howson, J.M.M.* ; Wareham, N.J.* ; Kastenmüller, G. ; Fauman, E.B.* ; Suhre, K.* ; Butterworth, A.S.* ; Langenberg, C.*

Rare and common genetic determinants of metabolic individuality and their effects on human health.

Nat. Med. 28, 2321-2332 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Genome-wide Association; Inborn-errors; Variants; Disease; Identification; Deficiency; Prediction; Imputation; Database; Kidney
Sprache englisch
Veröffentlichungsjahr 2022
HGF-Berichtsjahr 2022
ISSN (print) / ISBN 1078-8956
e-ISSN 1546-170X
Zeitschrift Nature medicine
Quellenangaben Band: 28, Heft: 11, Seiten: 2321-2332 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503891-001
Förderungen 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
DOI 10.1038/s41591-022-02046-0
WOS ID 000881574700007
WOS ID WOS:000881574700007
Scopus ID 85141709449
PubMed ID 36357675
Erfassungsdatum 2022-12-06
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