Blood-based gene expression signatures of medication-free outpatients with major depressive disorder: integrative genome-wide and candidate gene analyses.

Hiroaki Hori,Noriko Yamamoto,Toshiya Teraishi,Seiji Nakamura,Yoshiharu Kim,Kotaro Hattori,Miho Ota,Daimei Sasayama,Teruhiko Higuchi,Hiroshi Kunugi

doi:10.1038/srep18776

Abstract

Several microarray-based studies have investigated gene expression profiles in major depressive disorder (MDD), yet with highly variable findings. We examined blood-based genome-wide expression signatures of MDD, focusing on molecular pathways and networks underlying differentially expressed genes (DEGs) and behaviours of hypothesis-driven, evidence-based candidate genes for depression. Agilent human whole-genome arrays were used to measure gene expression in 14 medication-free outpatients with MDD who were at least moderately ill and 14 healthy controls matched pairwise for age and sex. After filtering, we compared expression of entire probes between patients and controls and identified DEGs. The DEGs were evaluated by pathway and network analyses. For the candidate gene analysis, we utilized 169 previously prioritized genes and examined their case-control separation efficiency and correlational co-expression network in patients relative to controls. The 317 screened DEGs mapped to a significantly over-represented pathway, the “synaptic transmission” pathway. The protein-protein interaction network was also significantly enriched, in which a number of key molecules for depression were included. The co-expression network of candidate genes was markedly disrupted in patients. This study provided evidence for an altered molecular network along with several key molecules in MDD and confirmed that the candidate genes are worthwhile targets for depression research.

Highlights

Overlap[10,11], and as such, peripheral blood gene expression is regarded as a reasonable surrogate that circumvents several limitations associated with postmortem brain tissue[9,12]
The reported differentially expressed genes (DEGs) have been highly variable across studies and, in general, most of the DEGs identified in one study have not been replicated in others[21]
Genetic research for Major depressive disorder (MDD) in the past few decades has extensively studied the so-called candidate genes for depression that were primarily chosen based on their biological mechanisms, such as genes involved in monoamine and glutamate neurotransmission, hypothalamic-pituitary-adrenal (HPA) axis function, and neurogenesis

Summary

Introduction

Overlap[10,11], and as such, peripheral blood gene expression is regarded as a reasonable surrogate that circumvents several limitations associated with postmortem brain tissue[9,12]. The stringent thresholds for a marker to be considered differentially expressed (that is, only those markers exceeding the thresholds adjusted for genome-wide error rate were selected as DEGs) may have contributed to the inconsistent findings This explanation is plausible given the relatively small sample sizes and large numbers of transcripts simultaneously tested, and as a result, even true susceptibility genes for depression that do not necessarily have such a large effect size could be buried in a sea of false negative findings. It would be of interest to test whether the hypothesis-driven, evidence-based candidate genes overall tend to be associated with depression, and, if so, which genes or gene networks are relevant Against these backgrounds, the present study set out to investigate blood-based genome-wide expression signatures in patients with MDD relative to healthy controls matched pairwise for age and sex. We were interested in inspecting the obtained results in the context of extant evidence in the literature

Methods

Results

Conclusion