Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression
Author(s)
Type
Journal Article
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.
Date Issued
2016-10-01
Date Acceptance
2016-08-15
Citation
American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 2016, 174 (3), pp.235-250
ISSN
1552-485X
Publisher
Wiley
Start Page
235
End Page
250
Journal / Book Title
American Journal of Medical Genetics Part B-Neuropsychiatric Genetics
Volume
174
Issue
3
Copyright Statement
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Sponsor
Engineering & Physical Science Research Council (EPSRC)
Grant Number
EP/K040723/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Psychiatry
machine learning
SVM
transcriptomics
antidepressants
SSRI
CONVERGENT FUNCTIONAL GENOMICS
ELEMENT-BINDING PROTEIN
FACTOR-KAPPA-B
MAJOR DEPRESSION
HIPPOCAMPAL NEUROGENESIS
MOLECULAR-MECHANISMS
WIDE ASSOCIATION
CANDIDATE GENES
DRUG-TREATMENT
FACTOR CREB
Animals
Antidepressive Agents
Citalopram
Cyclic AMP Response Element-Binding Protein
Depression
Depressive Disorder
Disease Models, Animal
Female
Hippocampus
Male
Mice
Multifactorial Inheritance
Nortriptyline
Pharmacogenetics
Serotonin Uptake Inhibitors
Serotonin and Noradrenaline Reuptake Inhibitors
Transcriptome
Treatment Outcome
0604 Genetics
1103 Clinical Sciences
1109 Neurosciences
Publication Status
Published