title: A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility.
abstract: Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood-brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted of ITGAL, ICAM1 and ICAM3 genes, could be of interest to develop novel therapeutic targets.
authors.affiliation: UPMC-INSERM-UMR_S 1127-CNRS UMR7225, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Damotte
authors.affiliation: UPMC-INSERM-UMR_S 1127-CNRS UMR7225, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Guillot-Noel
authors.affiliation: 1] Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham & Women's Hospital, Boston, MA, USA [2] Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA [3] Harvard Medical School, Boston, MA, USA [4] Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Patsopoulos
authors.affiliation: Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, San Francisco, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Madireddy
authors.affiliation: 1] UPMC-INSERM-UMR_S 1127-CNRS UMR7225, Paris, France [2] Institut du Cerveau et de la Moelle épinière-ICM, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: El Behi
authors.affiliation: 1] Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham & Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA [3] Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Department of Neurology, University of California at San Francisco, Sandler Neurosciences Center, San Francisco, CA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Baranzini
authors.affiliation: 1] UPMC-INSERM-UMR_S 1127-CNRS UMR7225, Paris, France [2] Assistance Publique-Hôpitaux de Paris (AP-HP), Département des Maladies du Systéme Nerveux, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Cournu-Rebeix
authors.affiliation: 1] UPMC-INSERM-UMR_S 1127-CNRS UMR7225, Paris, France [2] Assistance Publique-Hôpitaux de Paris (AP-HP), Département des Maladies du Systéme Nerveux, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Fontaine
mesh_terms: D015703:Antigens, CD / Q000235:genetics; D001812:Blood-Brain Barrier / Q000166:cytology / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; C573420:ICAM1 protein, human; C483616:ICAM3 protein, human; D039001:Integrin alpha Chains; D018799:Intercellular Adhesion Molecule-1