title: Neuronal cell adhesion genes and antidepressant response in three independent samples.
abstract: Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.
authors: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
authors: C
authors: C
authors: Fabbri
authors: Department of Biomedical Science and Morphological and Functional Images, University of Messina, Messina, Italy.
authors: C
authors: C
authors: Crisafulli
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Italy.
authors: D
authors: D
authors: Gurwitz
authors: Federal Institute for Drugs and Medical Devices, University Bonn Medical School, Bonn, Germany.
authors: J
authors: J
authors: Stingl
authors: Faculty Centre for Translational Medicine, University Bonn, Medical Faculty, Bonn, Germany.
authors: R
authors: R
authors: Calati
authors: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors: D
authors: http://orcid.org/0000-0002-7050-6723
authors: D
authors: Albani
authors: Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors: G
authors: G
authors: Forloni
authors: Department of Biomedical Science and Morphological and Functional Images, University of Messina, Messina, Italy.|Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors: M
authors: M
authors: Calabrò
authors: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.|Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.
authors: R
authors: R
authors: Martines
authors: Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.
authors: S
authors: S
authors: Kasper
authors: Department of Psychiatry, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: J
authors: J
authors: Zohar
authors: Department of Psychiatry, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: A
authors: A
authors: Juven-Wetzler
authors: Laboratoire de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, Belgium.
authors: D
authors: D
authors: Souery
authors: lmperial College School of Medicine, London, UK.
authors: S
authors: S
authors: Montgomery
authors: Université Libre de Bruxelles, Brussels, Belgium.
authors: J
authors: J
authors: Mendlewicz
authors: Faculty Centre for Translational Medicine, University Bonn, Medical Faculty, Bonn, Germany.
authors: G D
authors: GD
authors: Girolamo
authors: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
authors: A
authors: A
authors: Serretti
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D019922:GAP-43 Protein / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D000928:Antidepressive Agents; D015415:Biomarkers; C490650:CHL1 protein, human; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D019922:GAP-43 Protein; C061248:ITGB3 protein, human; D039661:Integrin beta3