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Lower performances in cognitive ability in individuals with Major Depressive Disorder (MDD) have been observed on multiple occasions. Understanding cognitive performance in MDD could provide a wider insight in the aetiology of MDD as a whole. Using a large, well characterised cohort ( N  = 7012), we tested for: differences in cognitive performance by MDD status and a gene (single SNP or polygenic score) by MDD interaction effect on cognitive performance. Linear regression was used to assess the association between cognitive performance and MDD status in a case-control, single-episode–recurrent MDD and control-recurrent MDD study design. Test scores on verbal declarative memory, executive functioning, vocabulary, and processing speed were examined. Cognitive performance measures showing a significant difference between groups were subsequently analysed for genetic associations. Those with recurrent MDD have lower processing speed versus controls and single-episode MDD ( β =   − 2.44,  p  = 3.6 × 10 −04 ;  β =   - 2.86,  p  = 1.8 × 10 −03 , respectively). There were significantly higher vocabulary scores in MDD cases versus controls ( β  = 0.79,  p  = 2.0 × 10 −06 ), and for recurrent MDD versus controls ( β  = 0.95,  p   =  5.8 × 10 −05 ). Observed differences could not be linked to significant single-locus associations. Polygenic scores created from a processing speed meta-analysis GWAS explained 1% of variation in processing speed performance in the single-episode versus recurrent MDD study ( p  = 1.7 × 10 −03 ) and 0.5% of variation in the control versus recurrent MDD study ( p  = 1.6 × 10 −10 ). Individuals with recurrent MDD showed lower processing speed and executive function while showing higher vocabulary performance. Within MDD, persons with recurrent episodes show lower processing speed and executive function scores relative to individuals experiencing a single episode.

Phenotypic and genetic analysis of cognitive performance in Major Depressive Disorder in the Generation Scotland: Scottish Family Health Study