Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results
Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results
SUMMARY Studies combining metabolomics and genetics, known as metabolite genome-wide association studies (mGWAS), have provided valuable insights into our understanding of the genetic control of metabolite levels. However, the biological interpretation of these associations remains challenging due to a lack of existing tools to annotate mGWAS gene-metabolite pairs beyond the use of conservative statistical significance threshold. Here, we computed the shortest reactional distance (SRD) based on the curated knowledge of the KEGG database to explore its utility in enhancing the biological interpretation of results from three independent mGWAS, including a case study on sickle cell disease patients. Results show that, in reported mGWAS pairs, there is an excess of small SRD values and that SRD values and p-values significantly correlate, even beyond the standard conservative thresholds. The added-value of SRD annotation is shown for identification of potential false negative hits, exemplified by the finding of gene-metabolite associations with SRD ≤1 that did not reach standard genome-wide significance cut-off. The wider use of this statistic as an mGWAS annotation would prevent the exclusion of biologically relevant associations and can also identify errors or gaps in current metabolic pathway databases. Our findings highlight the SRD metric as an objective, quantitative and easy-to-compute annotation for gene-metabolite pairs that can be used to integrate statistical evidence to biological networks.
Therrien-Laperriere Sandra、Lettre Guillaume、Poujol Rapha?l、Ashley-Koch Allison E.、Bartolucci Pablo、Des Rosiers Christine、Hussin Julie G.、Cherkaoui Sarah、Ilboudo Yann、Garrett Melanie E.、Ruiz Matthieu、Rioux John D.、Baron Cantin、Mehanna Pamela、Telen Marilyn J.
Montreal Heart InstituteMontreal Heart Institute||D¨|partement de M¨|decine, Universit¨| de Montr¨|alMontreal Heart InstituteDuke Molecular Physiology Institute, Duke University Medical CenterUniversit¨| Paris Est Cr¨|teil, H?pitaux Universitaires Henri Mondor, APHP, Sickle cell referral center ¨C UMGGR||Universit¨| Paris Est Cr¨|teil, IMRB, Laboratory of excellence LABEXD¨|partement de Biochimie et de M¨|decine Mol¨|culaire, Universit¨| de Montr¨|al||Montreal Heart Institute||D¨|partement de Nutrition, Universit¨| de Montr¨|alMontreal Heart Institute||D¨|partement de M¨|decine, Universit¨| de Montr¨|alMontreal Heart Institute||Division of Oncology and Children?ˉs Research Center, University Children?ˉs Hospital Zurich, University of Zurich||Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Universit¨| Paris-SaclayD¨|partement de Biochimie et de M¨|decine Mol¨|culaire, Universit¨| de Montr¨|al||Montreal Heart InstituteDuke Molecular Physiology Institute, Duke University Medical CenterMontreal Heart Institute||D¨|partement de Nutrition, Universit¨| de Montr¨|alD¨|partement de Biochimie et de M¨|decine Mol¨|culaire, Universit¨| de Montr¨|al||Montreal Heart Institute||D¨|partement de M¨|decine, Universit¨| de Montr¨|alD¨|partement de Biochimie et de M¨|decine Mol¨|culaire, Universit¨| de Montr¨|al||Montreal Heart InstituteMontreal Heart InstituteDivision of Hematology, Department of Medicine, Duke University Medical Center
医学研究方法基础医学生物科学研究方法、生物科学研究技术
mGWASKEGGbiological networksshortest reactional distanceannotation
Therrien-Laperriere Sandra,Lettre Guillaume,Poujol Rapha?l,Ashley-Koch Allison E.,Bartolucci Pablo,Des Rosiers Christine,Hussin Julie G.,Cherkaoui Sarah,Ilboudo Yann,Garrett Melanie E.,Ruiz Matthieu,Rioux John D.,Baron Cantin,Mehanna Pamela,Telen Marilyn J..Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results[EB/OL].(2025-03-28)[2025-05-03].https://www.biorxiv.org/content/10.1101/2023.03.22.533869.点此复制
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