Ma-Li Wong1, Mauricio Arcos-Burgos2, Sha Liu3, Alice W Licinio3, Chenglong Yu4, Eunice W M Chin5, Wei-Dong Yao6, Xin-Yun Lu7, Stefan R Bornstein8, Julio Licinio9. 1. Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, USA; Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY, USA; Mind & Brain Theme, South Australian Health and Medical Research Institute Adelaide, South Australia, Australia; Department of Psychiatry, Flinders University College of Medicine and Public Health, Bedford Park, South Australia, Australia. Electronic address: wongma@upstate.edu. 2. Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellin, Antioquia, Colombia. 3. Mind & Brain Theme, South Australian Health and Medical Research Institute Adelaide, South Australia, Australia. 4. Mind & Brain Theme, South Australian Health and Medical Research Institute Adelaide, South Australia, Australia; Department of Psychiatry, Flinders University College of Medicine and Public Health, Bedford Park, South Australia, Australia. 5. Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, USA. 6. Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, USA; Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY, USA. 7. Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA. 8. Medical Clinic III, Carl Gustav Carus University Hospital, Dresden University of Technology, Dresden, Germany. 9. Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, USA; Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY, USA; Mind & Brain Theme, South Australian Health and Medical Research Institute Adelaide, South Australia, Australia; Department of Psychiatry, Flinders University College of Medicine and Public Health, Bedford Park, South Australia, Australia. Electronic address: licinioJ@upstate.edu.
Abstract
INTRODUCTION: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response. METHOD: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes. RESULTS: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess. LIMITATIONS: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted. CONCLUSION: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response. TRIAL REGISTRATION: ClinicalTrials.gov NCT00265291.
INTRODUCTION: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response. METHOD: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes. RESULTS: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess. LIMITATIONS: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted. CONCLUSION: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response. TRIAL REGISTRATION: ClinicalTrials.gov NCT00265291.
Authors: R Jansen; B W J H Penninx; V Madar; K Xia; Y Milaneschi; J J Hottenga; A R Hammerschlag; A Beekman; N van der Wee; J H Smit; A I Brooks; J Tischfield; D Posthuma; R Schoevers; G van Grootheest; G Willemsen; E J de Geus; D I Boomsma; F A Wright; F Zou; W Sun; P F Sullivan Journal: Mol Psychiatry Date: 2015-05-26 Impact factor: 15.992
Authors: Nicholas A Johnson; Marc A Coram; Mark D Shriver; Isabelle Romieu; Gregory S Barsh; Stephanie J London; Hua Tang Journal: PLoS Genet Date: 2011-12-15 Impact factor: 5.917