Clinical genetics; Human genetics; Pathophysiology; Multidisciplinary
Abstract :
[en] Population-scale datasets of healthy individuals capture genetic and environmental factors influencing gene expression. The expression variance of a gene of interest (GOI) can be exploited to set up a quasi loss- or gain-of-function "in population" experiment. We describe here an approach, huva (human variation), taking advantage of population-scale multi-layered data to infer gene function and relationships between phenotypes and expression. Within a reference dataset, huva derives two experimental groups with LOW or HIGH expression of the GOI, enabling the subsequent comparison of their transcriptional profile and functional parameters. We demonstrate that this approach robustly identifies the phenotypic relevance of a GOI allowing the stratification of genes according to biological functions, and we generalize this concept to almost 16,000 genes in the human transcriptome. Additionally, we describe how huva predicts monocytes to be the major cell type in the pathophysiology of STAT1 mutations, evidence validated in a clinical cohort.
Disciplines :
Genetics & genetic processes
Author, co-author :
Bonaguro, Lorenzo; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany ; Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53113 Bonn, Germany
Schulte-Schrepping, Jonas; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany ; Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53113 Bonn, Germany
Carraro, Caterina; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany ; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
Sun, Laura L; Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53113 Bonn, Germany
Gemünd, Ioanna; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany ; Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53113 Bonn, Germany ; Department of Microbiology and Immunology, the University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville, 3010 VIC, Australia
Saglam, Adem; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
Rahmouni, Souad ; Université de Liège - ULiège > GIGA > GIGA Medical Genomics - Unit of Animal Genomics
Georges, Michel ; Université de Liège - ULiège > GIGA > GIGA Innovation
Arts, Peer; Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands ; Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, 5000 SA, Australia
Hoischen, Alexander; Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 Nijmegen, the Netherlands ; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 Nijmegen, the Netherlands
Joosten, Leo A B; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 Nijmegen, the Netherlands ; Department of Medical Genetics, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
van de Veerdonk, Frank L; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 Nijmegen, the Netherlands
Netea, Mihai G; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 Nijmegen, the Netherlands ; Immunology and Metabolism, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53113 Bonn, Germany
Händler, Kristian; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany ; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), PRECISE Platform for Genomics and Epigenomics at DZNE and University of Bonn, 53127 Bonn, Germany
Mukherjee, Sach; Statistics and Machine Learning, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany ; MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK
Ulas, Thomas; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany ; Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53113 Bonn, Germany ; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), PRECISE Platform for Genomics and Epigenomics at DZNE and University of Bonn, 53127 Bonn, Germany
Schultze, Joachim L; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany ; Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53113 Bonn, Germany ; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), PRECISE Platform for Genomics and Epigenomics at DZNE and University of Bonn, 53127 Bonn, Germany
Aschenbrenner, Anna C ; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany ; Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, 53113 Bonn, Germany ; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525 Nijmegen, the Netherlands
DFG - German Research Foundation BMBF - Bundesministerium für Bildung und Forschung NWO - Netherlands Organisation for Scientific Research Europäische Kommission
Funding text :
We thank T. Pecht and T. Kappellos for the critical revision of the huva framework and M. Kraut, H. Theis for technical assistance. The work was supported by the German Research Foundation (DFG) to J.L.S. under Germany’s Excellence Strategy ( EXC2151-390873048 ) as well as under SCHU 950/8-1 ; GRK 2168 , TP11 ; SFB704 , the BMBF -funded excellence project Diet-Body-Brain (DietBB) and the EU project SYSCID under grant number 733100 . A.C.A. was supported by an intramural grant from the Department of Genomics & Immunoregulation at the LIMES Institute . M.G.N. was supported by a Spinoza grant of the Netherlands Organization for Scientific Research and an ERC Advanced Grant ( 833247 ).
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