Peripheral blood gene expression analysis implicates B lymphocyte proliferation and ribosomal S26 transcripts in cognitive dysfunction in people with remitted Major Depression

Abstract

Residual impairments in cognitive domains including attention, memory, executive function, and social perception occur in about 40% of patients with Major Depressive Disorder (MDD) following remission from acute episodes (Conradi et al., 2011), and are associated with reductions in pre-morbid functioning and higher unemployment rates (Baune et al., 2010; Evans et al., 2014). Cognitive impairment in MDD may represent a trait marker, trait-byillness interaction marker, or endophenotype of MDD that is independent of the acute depressive state and particularly active in a subgroup of MDD patients (Hasler et al., 2004; Iverson et al., 2011). We explored the potential molecular underpinnings of such a ‘cognitive’ MDD phenotype in a well-matched pilot sample of remitted MDD patients with poorer versus better performance on cognitive testing. Because the phenotype is likely highly complex, polygenic, and heterogeneous, we performed weighted gene coexpression network analysis (WGCNA), a hypothesis-free systems biology approach that identifies ‘modules’ of co-regulated – and therefore functionally related – genes in transcriptomic datasets. After constructing a gene co-expression network from samples of all patients, we determined whether modules were correlated with poorer versus better cognitive performance. We additionally explored whether modules were also correlated with a continuous measure of cognitive performance in both groups. We utilized whole blood transcriptomic data from remitted MDD patients from the Adelaide Cognitive Function and Mood Study (CoFaMS, HREC RAH protocol no. 111230g) matched for race, gender, age, Hamilton Depression Scale score, presence of psychotic features during any depressive episode, educational status, annual household income, current drugand alcohol use, and