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Neuronal cell adhesion genes and antidepressant response in three independent samples

The Pharmacogenomics Journal volume 15, pages 538–548 (2015)Cite this article

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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.

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Acknowledgements

The present study was supported by the grant: Pharmacogenomics of Antidepressant Drug ResponsE (PADRE): tentative drug response biomarkers from human lymphoblastoid cells from ERA-NET NEURON. Data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported ‘Sequenced Treatment Alternatives to Relieve Depression’ (STAR*D). STAR*D focused on non-psychotic major depressive disorder in adults seen in outpatient settings. The primary purpose of this research study was to determine which treatments work best if the first treatment with medication does not produce an acceptable response. The study was supported by NIMH Contract # N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528.

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Authors and Affiliations

  1. Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy

    C Fabbri, R Martines & A Serretti

  2. Department of Biomedical Science and Morphological and Functional Images, University of Messina, Messina, Italy

    C Crisafulli & M Calabrò

  3. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Italy

    D Gurwitz

  4. Federal Institute for Drugs and Medical Devices, University Bonn Medical School, Bonn, Germany

    J Stingl

  5. Faculty Centre for Translational Medicine, University Bonn, Medical Faculty, Bonn, Germany

    R Calati & G D Girolamo

  6. Department of Neuroscience, Laboratory of Biology of Neurodegenerative Disorders, IRCCS Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy

    D Albani, G Forloni & R Martines

  7. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    M Calabrò

  8. Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria

    S Kasper

  9. Department of Psychiatry, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    J Zohar & A Juven-Wetzler

  10. Laboratoire de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, Belgium

    D Souery

  11. lmperial College School of Medicine, London, UK

    S Montgomery

  12. Université Libre de Bruxelles, Brussels, Belgium

    J Mendlewicz

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Correspondence to A Serretti.

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Competing interests

AS is or has been a consultant/speaker for: Abbott, Astra Zeneca, Clinical Data, Boehringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Pfizer, Sanofi and Servier. All other authors declare no conflict of interest.

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Fabbri, C., Crisafulli, C., Gurwitz, D. et al. Neuronal cell adhesion genes and antidepressant response in three independent samples. Pharmacogenomics J 15, 538–548 (2015). https://doi.org/10.1038/tpj.2015.15

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