Dissecting genetic regulation of metabolic coordination
Year: 2025
Type: article
Abstract: Understanding genetic regulation of metabolism is critical for gaining insights into the causes of metabolic diseases. Traditional metabolome-based genome-wide association studies (mGWAS) focus on static associations between single nucleotide polymorphisms (SNPs) and metabolite levels, overlooking the changing relationships caused by genotypes within the metabolic network. Notably, some metabolites exhibit changes in correlation patterns with other metabolites under certain physiological conditions while maintaining their overall abundance level. In this manuscript, we develop Metabolic Differential-coordination GWAS (mdGWAS), an innovative framework that detects SNPs associated with the changing correlation patterns between metabolites and metabolic pathways. This approach transcends and complements conventional mean-based analyses by identifying latent regulatory factors that govern the system-level metabolic coordination. Through comprehensive simulation studies, mdGWAS demonstrated robust performance in detecting SNP-metabolite-metabolite associations. Applying mdGWAS to genotyping and mass spectrometry (MS)-based metabolomics data of the METabolic Syndrome In Men (METSIM) Study revealed novel SNPs and genes potentially involved in the regulation of the coordination between metabolic pathways.
Source: UNC Libraries
DOI: 10.17615/qh1g-w427
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, John Templeton Foundation, Brown University, Japan Agency for Medical Research and Development, Wellcome Trust, Collaborative Research in Engineering, Science and Technology Centre, Finnish Cancer Institute, National Institute for Health and Care Research, British Heart Foundation, European Commission, Indian Council of Medical Research, Deutsche Forschungsgemeinschaft, National Natural Science Foundation of China, ZonMw, Austrian Science Fund, Jiangsu University, Fonds Wetenschappelijk Onderzoek, Ministero della Salute, Natural Science Foundation of Hubei Province, Päivikki ja Sakari Sohlbergin Säätiö, Princess Nourah Bint Abdulrahman University, Vetenskapsrådet, Türkiye Bilimsel ve Teknolojik Araştırma Kurumu, China Scholarship Council, Göteborgs Läkaresällskap, Sigrid Juséliuksen Säätiö, Xi’an Jiaotong-Liverpool University, Russian Science Foundation, Orionin Tutkimussäätiö, Universitätsklinikum Jena, Uniwersytet Rzeszowski, Kao Corporation, Novo Nordisk Fonden, Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España, Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, Xinxiang Medical University, Higher Education Discipline Innovation Project, Sahlgrenska University Hospitals Research Foundations, General Sir John Monash Foundation, National Institutes of Health, School of Medicine, Indiana University, National Outstanding Youth Science Fund Project of National Natural Science Foundation of China, Qatar National Library, Canadian Institutes of Health Research, Engineering and Physical Sciences Research Council, Leibniz-Gemeinschaft, Japan Society for the Promotion of Science, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities, National Key Clinical Specialty Discipline Construction Program of China, Technische Universität Wien Bibliothek, National Institute of Mental Health, NIH Office of the Director, National Institute on Deafness and Other Communication Disorders, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Office of AIDS Research, Basic Energy Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, H2020 European Research Council, NHLBI Division of Intramural Research, Biological Technologies Office
OpenAlex ID: W7166648089