title: Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression.
abstract: Response to antidepressant (AD) treatment may be a more polygenic trait than previously hypothesized, with many genetic variants interacting in yet unclear ways. In this study we used methods that can automatically learn to detect patterns of statistical regularity from a sparsely distributed signal across hippocampal transcriptome measurements in a large-scale animal pharmacogenomic study to uncover genomic variations associated with AD. The study used four inbred mouse strains of both sexes, two drug treatments, and a control group (escitalopram, nortriptyline, and saline). Multi-class and binary classification using Machine Learning (ML) and regularization algorithms using iterative and univariate feature selection methods, including InfoGain, mRMR, ANOVA, and Chi Square, were used to uncover genomic markers associated with AD response. Relevant genes were selected based on Jaccard distance and carried forward for gene-network analysis. Linear association methods uncovered only one gene associated with drug treatment response. The implementation of ML algorithms, together with feature reduction methods, revealed a set of 204 genes associated with SSRI and 241 genes associated with NRI response. Although only 10% of genes overlapped across the two drugs, network analysis shows that both drugs modulated the CREB pathway, through different molecular mechanisms. Through careful implementation and optimisations, the algorithms detected a weak signal used to predict whether an animal was treated with nortriptyline (77%) or escitalopram (67%) on an independent testing set. The results from this study indicate that the molecular signature of AD treatment may include a much broader range of genomic markers than previously hypothesized, suggesting that response to medication may be as complex as the pathology. The search for biomarkers of antidepressant treatment response could therefore consider a higher number of genetic markers and their interactions. Through predominately different molecular targets and mechanisms of action, the two drugs modulate the same Creb1 pathway which plays a key role in neurotrophic responses and in inflammatory processes. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry Centre at the Institute of Psychiatry, Psychology and Neuroscience (IOPPN), London, United Kingdom.
authors.forename: Karim
authors.initials: K
authors.lastname: Malki
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry Centre at the Institute of Psychiatry, Psychology and Neuroscience (IOPPN), London, United Kingdom.|LCIBG, Tomsk State University, Tomsk, Russia.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tosto
authors.affiliation: Department of Computer Science, UCL, London, United Kingdom.
authors.forename: Héctor
authors.initials: H
authors.lastname: Mouriño-Talín
authors.affiliation: Division of Medicine, UCL, London, United Kingdom.
authors.forename: Sabela
authors.initials: S
authors.lastname: Rodríguez-Lorenzo
authors.affiliation: Birkbeck, University of London, United Kingdom.|London School of Hygiene & Tropical Medicine, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Pain
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry Centre at the Institute of Psychiatry, Psychology and Neuroscience (IOPPN), London, United Kingdom.
authors.forename: Irfan
authors.initials: I
authors.lastname: Jumhaboy
authors.affiliation: Department of Computer Science Imperial College London, United Kingdom.
authors.forename: Tina
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Computer Science Imperial College London, United Kingdom.
authors.forename: Panos
authors.initials: P
authors.lastname: Parpas
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry Centre at the Institute of Psychiatry, Psychology and Neuroscience (IOPPN), London, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Newman
authors.affiliation: LCIBG, Tomsk State University, Tomsk, Russia.
authors.forename: Artem
authors.initials: A
authors.lastname: Malykh
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Bologna, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Carboni
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry Centre at the Institute of Psychiatry, Psychology and Neuroscience (IOPPN), London, United Kingdom.|Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Uher
authors.affiliation: King's College London, MRC Social, Genetic and Developmental Psychiatry Centre at the Institute of Psychiatry, Psychology and Neuroscience (IOPPN), London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: McGuffin
authors.affiliation: School of Biological Sciences, University of Essex, Colchester, United Kingdom.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Schalkwyk
authors.affiliation: Department of Computer Science, UCL, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bryson
authors.affiliation: Department of Computer Science, UCL, London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Herbster
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D015283:Citalopram / Q000627:therapeutic use; D017362:Cyclic AMP Response Element-Binding Protein; D003863:Depression / Q000188:drug therapy; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus; D008297:Male; D051379:Mice; D020412:Multifactorial Inheritance / Q000235:genetics; D009661:Nortriptyline / Q000627:therapeutic use; D010597:Pharmacogenetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D059467:Transcriptome / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D017362:Cyclic AMP Response Element-Binding Protein; D009661:Nortriptyline; D017367:Selective Serotonin Reuptake Inhibitors; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; C492004:Creb1 protein, mouse
keywords: SSRI; SVM; antidepressants; machine learning; transcriptomics