Polygenic risk scores for major depressive disorder and neuroticism as predictors of antidepressant response: Meta-analysis of three treatment cohorts.

Cathryn M. Lewis,Joey Ward,Joanna Biernacka,Rona J. Strawbridge,Mark Frye,Wenan Chen,Karen Hodgson,Rudolf Uher,Richard Weinshilboum,Amy Ferguson,Gregory Jenkins,Daniel J. Smith,Nicholas Graham

doi:10.1371/journal.pone.0203896

Abstract

There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 760). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10–5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, β = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.

Highlights

Major Depressive disorder (MDD) is a leading cause of disability worldwide [1]
Full genotyping and imputation methodology in Genome-based Therapeutic Drugs for Depression (GENDEP) is described in previous reports [15]
Most of the findings were null, there was a direction of effect where higher Polygenic Risk Scores (PRS) for major depressive disorder (MDD) and higher PRS for neuroticism were associated with less favourable response to Selective Serotonin Reuptake Inhibitors (SSRIs)

Summary

Introduction

Major Depressive disorder (MDD) is a leading cause of disability worldwide [1]. Antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs) are first line treatments for MDD but up to one third of patients do not respond satisfactorily [2, 3]. Does genetic loading for major depressive disorder and neuroticism impact the efficacy of anti-depressants?. Strawbridge), MRC Doctoral Training Programme (Grant MR/K501335/1 to Ms Amy Ferguson), National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London to Prof Cathryn Lewis.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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