Identification of genes and gene pathways associated with major depressive disorder by integrative brain analysis of rat and human prefrontal cortex transcriptomes.

K Malki,M G Tosto,E Du Rietz,L C Schalkwyk,L Carboni,O Pain

doi:10.1038/tp.2015.15

K Malki, M G Tosto + Show 4 more

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https://doi.org/10.1038/tp.2015.15

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Abstract

Despite moderate heritability estimates, progress in uncovering the molecular substrate underpinning major depressive disorder (MDD) has been slow. In this study, we used prefrontal cortex (PFC) gene expression from a genetic rat model of MDD to inform probe set prioritization in PFC in a human post-mortem study to uncover genes and gene pathways associated with MDD. Gene expression differences between Flinders sensitive (FSL) and Flinders resistant (FRL) rat lines were statistically evaluated using the RankProd, non-parametric algorithm. Top ranking probe sets in the rat study were subsequently used to prioritize orthologous selection in a human PFC in a case–control post-mortem study on MDD from the Stanley Brain Consortium. Candidate genes in the human post-mortem study were then tested against a matched control sample using the RankProd method. A total of 1767 probe sets were differentially expressed in the PFC between FSL and FRL rat lines at (q⩽0.001). A total of 898 orthologous probe sets was found on Affymetrix's HG-U95A chip used in the human study. Correcting for the number of multiple, non-independent tests, 20 probe sets were found to be significantly dysregulated between human cases and controls at q⩽0.05. These probe sets tagged the expression profile of 18 human genes (11 upregulated and seven downregulated). Using an integrative rat–human study, a number of convergent genes that may have a role in pathogenesis of MDD were uncovered. Eighty percent of these genes were functionally associated with a key stress response signalling cascade, involving NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), AP-1 (activator protein 1) and ERK/MAPK, which has been systematically associated with MDD, neuroplasticity and neurogenesis.

Highlights

Major depressive disorder (MDD) is a severe psychiatric disease providing a significant contribution to the global burden of disease.[1,2] Endeavours to identify factors underlying the molecular basis of MDD have been guided by quantitative studies reporting a substantial genetic contribution to its development.[3]
The analysis of differential gene expression in the prefrontal cortex (PFC) of individuals diagnosed with MDD or controls, using the candidate gene selection, provided a list of genes and biological pathways associated with MDD
Ingenuity Pathway Analysis (IPA) identified a functional pathway involving 80% of the genes significantly associated with MDD in humans (Figure 1)

Summary

Introduction

Major depressive disorder (MDD) is a severe psychiatric disease providing a significant contribution to the global burden of disease.[1,2] Endeavours to identify factors underlying the molecular basis of MDD have been guided by quantitative studies reporting a substantial genetic contribution to its development.[3]. One approach for studying the molecular mechanism of MDD in disease-relevant brain regions is by exploring messenger RNA (mRNA) changes in animal models.[6] The identification of differentially expressed genes can provide early clues into the molecular mechanisms associated with the pathology in humans. The exploration of the human brain transcriptome has major limitations, namely the sample limitations, including the requirement of post-mortem brain tissue and confounding factors.[7] several studies have demonstrated the advantage of using animal models of disease to inform human studies by providing a hypothesis-free candidate genes selection with higher prior probability of being involved in the human pathology.[6,8,9]

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