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New Insights from Cell Adhesion Molecules In New insights from cell adhesion molecules in antidepressant action: role of ITGB3 and GAP43 genes Chiara Fabbri1, Rosalba Martines1,5, Concetta Crisafulli4, David Gurwitz2, Julia Stingl3, Raffaella Calati1, Diego Albani5, Armando Chierchia5, Edoardo Spina6, Marco Calabrò4,6, Siegfried Kasper7, Marie Spies7, Joseph Zohar8, Alzbeta Juven-Wetzler8, Daniel Souery9, Stuart Montgomery10, Julien Mendlewicz11, Alessandro Serretti1 1: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy 7: Department of Psychiatry and Psychotherapy, Medical University Vienna, Austria 2: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University 8: Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, 3: Bundesinstitut für Arzneimittel und Medizinprodukte, Translationale Pharmakologie, Universität Bonn Tel Aviv University, Israel 4: Department of Biomedical Science and morphological and functional images, University of Messina, Italy 9: Laboratoire de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Centre 5: Unit of Genetics of Neurodegenerative DisordersNeuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Européen de Psychologie Medicale, Brussels Negri", Milan, Italy 10: lmperial College School of Medicine, London, UK 6: Department of Clinical and Experimental Medicine, University of Messina, Italy 11: Universite´ Libre de Bruxelles Adhesion proteins implicated in TO INVESTIGATE ITGB3 AND neuronal plasticity and axonal Regulation of serotonergic GAP43 GENETIC VARIANTS AND guidance neurotransmission MOLECULAR PATHWAYS IN ANTIDEPRESSANT EFFICACY IN AIMS HUMANS Altered expression in LCLs exposed to paroxetine [2] Correlation with CHL1, previously implicated in antidepressant efficacy [1] METHODS: 10 tag SNPs in GAP43 and ITGB3 were genotyped in two independent samples (European n=373 and Italian n=96) of patients with major depression who were treated with antidepressants in a naturalistic setting. Phenotypes were response and remission at week 4 and treatment resistant depression (TRD) in the largest sample. TRD was defined as non response to at least 2 adequate consecutive antidepressant treatments during the last episode (TRDW) or non response to at least 2 adequate consecutive antidepressant drugs of different classes (TRDC). The genes were investigated in the STAR*D GWAS (n=1892) in order to replicate findings. Logistic regression was applied; gender and age were used as covariates in all analyses, baseline severity and ethnicity were used as necessary. Finally, GAP43 and ITGB3 molecular pathways (Reactome or String databases) were investigated. Genes belonging to the pathway under analysis were imputed (IMPUTE2 software) and variations with p<0.05 and p<0.01 in the index pathway were tested for a different distribution compared to a random pathway (Fisher exact test; 10e04 permutations). RESULTS Genotyped SNPs European sample Italian sample Trend of association between rs2056131 AA and non Gene Tag SNP Role Relative Position AA change MAF remission (genotypic p=0.09) GAP43 rs2028248 Intronic 24816 None 0.41 Gene -SNP P HWE Response Remission TRDW - TRDC GAP43 rs283393 Intronic 81079 None 0.47 ITGB3 - 0.17 NS Genotypic p=0.009 NS rs15908 Allelic p=0.03 GAP43 rs3827496 Promoter -1251 None 0.44 ITGB3 - 0.51 NS Genotypic p=0.02 NS GAP43 rs6803101 Intronic 13814 None 0.30 rs2056131 Allelic p=0.27 GAP43 rs9860828 Intronic 43532 None 0.39 GAP43 - 0.82 NS Genotypic p=0.02 NS ITGB3 rs15908 Exonic 37130 381 V/V 0.33 rs283393 Allelic p=0.03 ITGB3 rs2056131 Intronic 2536 None 0.31 GAP43 - 0.22 NS Genotypic p=0.005 NS ITGB3 rs3809865 3' UTR 57379 None 0.33 rs2028248 Allelic p=0.03 ITGB3 rs3851807 Intronic 20312 None 0.35 GAP43 - 0.89 Genotypic p=0.03 NS Allelic p=0.02 ITGB3 rs8074094 Intronic 16814 None 0.27 rs9860828 Allelic p=0.0088 Allelic p=0.02 STAR*D sample 52 and 34 SNPs available in GAP43 Results after imputation in the STAR*D and ITGB3, respectively GAP43 ITGB3 ITGB3 rs11655536 trend of association with remission (p=0.047) ~9000 bp from rs12490536 5696 bp from rs2056131 and ~18 Kbp from rs9860828 GAP43 SNP Response Remission bp from rs9860828 rs12488667 p=0.003 NS 889 rs4831199 p=0.03 NS 1328 rs11926976 NS p=0.003 8611 rs283393 NS p=0.02 - GAP43 String Pathway Permutated p=0.017 for w4 response Permutated p=0.0054 for w4 remission 17/30 (56.67%) SNPs with CONCLUSION p<0.05 (w4 remission) The present study confirms a role of the CHL1 pathway in antidepressant response. GAP43 rs283393 and rs9860828-rs12488667 appear particularly interesting since their replication across samples. 24/112 (21.43%) SNPs ELAVL4 is a neuron-specific RNA binding protein involved in neuronal plasticity, learning and with p<0.05 (w4 remission) memory [3] that seems promising for further investigation. 242/1280 (18.91%) SNPs with p<0.05 (w4 remission) No conflict of interest. References: [1] Fabbri et al. Eur Neuropsychopharmacol. 23: S168-S169. [2] Oved el al. Transl Psychiatry. 2013 Oct 15;3:e313. [3] Bronicki and Jasmin. RNA. 2013 Aug;19(8):1019-37. P.1.a.012 New insights from cell adhesion molecules in antidepressant action: role of ITGB3 and GAP43 genes C. Fabbri1, C. Crisafulli2, D. Gurwitz3, J. Stingl4, R. Calati1, D. Albani5, A. Chierchia5, E. Spina6, M. Calabrò7, S. Kasper8, M. Spies8, J. Zohar9, A. Juven-Wetzler9, D. Souery10, S. Montgomery11, J. Mendlewicz12, A. Serretti1 1University of Bologna, Department of Biomedical and NeuroMotor Sciences, Bologna, Italy 2University of Messina, Department of Biomedical Science and morphological and functional images, Messina, Italy 3Tel-Aviv University, Department of Human Molecular Genetics and Biochemistry, Tel-Aviv, Israel 4Universität Bonn, Bundesinstitut für Arzneimittel und Medizinprodukte Translationale Pharmakologie, Bonn, Germany 5IRCCS Istituto di Ricerche Farmacologiche aMario Negria, Unit of Genetics of Neurodegenerative DisordersNeuroscience Department, Milano, Italy 6University of Messina, Department of Clinical and Experimental Medicine, Messina, Italy 7University of Messina, Department of Clinical and Experimental Medicine Department of Biomedical Science and morphological and functional images, Messina, Italy 8Medical University Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria 9Tel Aviv University, Department of Psychiatry Sheba Medical Center Tel Hashomer and Sackler School of Medicine, Tel-Aviv, Israel 10Université Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, Belgium 11University of London, lmperial College School of Medicine, London, United Kingdom 12Université Libre de Bruxelles, Department of Psychiatry, Brussels, Belgium Transcriptom ic profile in lymphoblastoid cell lines aLCLs) exposed in vitro to antidepressants has becam e a very useful and easily accessible surrogate of drug effect in the brain, given its correlation with gene expression in rat neuronal cells during antidepressant treatment. Genome-wide expression profiling in LCLs pointed to a key role of interacting adhesion proteins implicated in neuronal plasticity and axonal guidance, i.e. CHL1 acell adhesion molecule L1-like1), ITGB3 aintegrin beta-3) and GAP43 agrowth associated protein 43) in antidepressant action [1,2]. After pharmacogenetic evidence supporting the involvem ent of CHL1 [3], the present study aimed to investigate further this molecular pathway analyzing the role of ITGB3 and GAP43 in antidepressant efficacy. For this purpose 10 tag SNPs in GAP43 ars2028248, rs283393, rs3827496, rs6803101, rs9860828) and ITGB3 ars15908, rs2056131, rs3809865, rs3851807, rs8074094) were genotyped in two independent sam ples an=373: 275 with unipolar and 86 with bipolar depression; n=96: all with unipolar depression) of Caucasian patients with major depression. Patients were treated with antidepressant drugs in a naturalistic setting. Phenotypes were response and rem ission at week 4, besides resistance to treatment aTRD) in the largest sample. TRD was defined as non response to at least 2 adequate consecutive antidepressant treatments during the last episode aTRDW) or non response to at least 2 adequate consecutive antidepressant drugs of different classes during the last episode aTRDC). Logistic regression models were applied; covariates were selected according to their impact on outcomes. Secondly, the candidate genes were investigated in the Sequenced Treatment Alternatives to Relieve Depression aSTAR*D) genome-wide an=1861) before and after imputation. Imputation was performed using IMPUTE2 and CEU HapMap NCBI Build 36 adbSNP b126) as reference. In the largest original sam ple, ITGB3 rs15908 agenotypic p=0.009, allelic p=0.03), GAP43 rs283393 agenotypic p=0.02, allelic p=0.03) and rs2028248 agenotypic p=0.005, allelic p=0.03) were predictors of remission in unipolar depression. GAP43 rs9860828 was associated with response agenotypic p=0.03, allelic p=0.0088) and represented a putative predictor of TRDW aallelic p=0.02) and TRDC aallelic p=0.02) in the sam e sample. The only SNP showing a trend of replication between the two original sample was ITGB3 rs2056131 aremission: genotypic p=0.02 and p=0.09 in the largest and smallest sample, respectively). In the STAR*D, GAP43 rs12488667 a889 bp from rs9860828) and rs4831199 a1328 bp from rs9860828) were the top SNPs regarding response ap=0.003 and 0.03, respectively). GAP43 rs11926976, rs283393 and ITGB3 rs11655536 were associated with remission ap=0.003, 0.02 and 0.047, respectively).
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