Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results.

Autor:	Baron C; Département de Biochimie et de Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada.; Montreal Heart Institute, Montréal, QC, Canada., Cherkaoui S; Montreal Heart Institute, Montréal, QC, Canada.; Division of Oncology and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.; Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France., Therrien-Laperriere S; Montreal Heart Institute, Montréal, QC, Canada., Ilboudo Y; Département de Biochimie et de Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada.; Montreal Heart Institute, Montréal, QC, Canada., Poujol R; Montreal Heart Institute, Montréal, QC, Canada., Mehanna P; Montreal Heart Institute, Montréal, QC, Canada., Garrett ME; Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA., Telen MJ; Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC, USA., Ashley-Koch AE; Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA., Bartolucci P; Université Paris Est Créteil, Hôpitaux Universitaires Henri Mondor, APHP, Sickle cell referral center - UMGGR, Créteil, France.; Université Paris Est Créteil, IMRB, Laboratory of excellence LABEX, Créteil, France., Rioux JD; Département de Biochimie et de Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada.; Montreal Heart Institute, Montréal, QC, Canada.; Département de Médecine, Université de Montréal, Montréal, QC, Canada., Lettre G; Montreal Heart Institute, Montréal, QC, Canada.; Département de Médecine, Université de Montréal, Montréal, QC, Canada., Rosiers CD; Département de Biochimie et de Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada.; Montreal Heart Institute, Montréal, QC, Canada.; Département de Nutrition, Université de Montréal, Montréal, QC, Canada., Ruiz M; Montreal Heart Institute, Montréal, QC, Canada.; Département de Nutrition, Université de Montréal, Montréal, QC, Canada., Hussin JG; Montreal Heart Institute, Montréal, QC, Canada.; Département de Médecine, Université de Montréal, Montréal, QC, Canada.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2023 Nov 14; Vol. 26 (12), pp. 108473. Date of Electronic Publication: 2023 Nov 14 (Print Publication: 2023).
DOI:	10.1016/j.isci.2023.108473
Abstrakt:	Metabolite genome-wide association studies (mGWAS) have advanced our understanding of the genetic control of metabolite levels. However, interpreting these associations remains challenging due to a lack of tools to annotate gene-metabolite pairs beyond the use of conservative statistical significance threshold. Here, we introduce the shortest reactional distance (SRD) metric, drawing from the comprehensive KEGG database, to enhance the biological interpretation of mGWAS results. We applied this approach to three independent mGWAS, including a case study on sickle cell disease patients. Our analysis reveals an enrichment of small SRD values in reported mGWAS pairs, with SRD values significantly correlating with mGWAS p values, even beyond the standard conservative thresholds. We demonstrate the utility of SRD annotation in identifying potential false negatives and inaccuracies within current metabolic pathway databases. Our findings highlight the SRD metric as an objective, quantitative and easy-to-compute annotation for gene-metabolite pairs, suitable to integrate statistical evidence to biological networks. Competing Interests: J.G.H. received speaker honoraria from Dalcor and District 3 Innovation Centre. C.D.R. received research support from Agilent Technologies and is a scientific consultant for Larimar Therapeutics. P.B. is consultant for ADDMEDICA, NOVARTIS, ROCHE, GBT, Bluebird, EMMAUS, HEMANEXT, AGIOS, VERTEX, received lecture fees for NOVARTIS, ADDMEDICA, AGIOS, JAZZPHARMA, VERTEX, is on steering committee for NOVARTIS and ADDMEDICA, receives research support from ADDMEDICA, foundation Fabre, NOVARTIS, Bluebird, EMMAUS, GBT, and is cofounder of INNOVHEM. (© 2023 The Authors.)
Databáze:	MEDLINE
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