Investigating the association of the plasma lipidomic profile with cognitive performance and genetic risk in the PsyCourse study

Abstract

Although lipid biology may play a key role in the pathophysiology of mental health disorders such as schizophrenia (SCZ) and bipolar disorder (BD), the nature of this interplay and how it could shape phenotypic presentation, including cognitive performance is still incompletely understood. To address this question, we analyzed the association of plasma level of different lipid species with cognitive performance in the transdiagnostic PsyCourse Study. Plasma lipidomic profiles of 623 individuals (188 SCZ, 243 BD, 192 healthy controls) belonging to the PsyCourse Study were assessed using liquid chromatography and untargeted mass spectrometry. The association between 364 annotated lipid species from 16 lipid classes and six cognitive tests was evaluated. Likewise, the association of polygenic risk scores (PRS) for SCZ, BD, executive function (EF), and educational attainment (EA) with lipid plasma levels were also investigated. In the regression analysis, three lipid species belonging to phosphatidylethanolamine plasmalogen and one belonging to ceramide class showed significant negative association with Digit-Symbol test scores. Lipid class-based enrichment analysis in LipidR replicated the significance of the phosphatidylethanolamines class for the Digit-Symbol test, which evaluates the processing speed in cognitive tasks. Polygenic load for SCZ, BD, EF, or EA was not associated with lipid levels. Our findings suggest a link between lipids and cognitive performance independent of mental health disorders. Still, independent replication is warranted to better understand if phosphatidylethanolamines could represent an actionable pharmacologic target to tackle cognitive dysfunction, an important unmet clinical need that affects long-term functional outcomes in individuals with severe mental health disorders.

Fig. 1. No major effect of mental health diagnosis (schizophrenia, bipolar disorder, healthy control) as a covariate in regression model on significance of PE class for the DG-SYM test in lipid class-based enrichment analysis in lipidR.

Distribution of log fold change (logFC) per lipid class, with significantly enriched classes (marked in red) for mean-based low (as seen in the plots) versus high results in the dataset including all individuals with schizophrenia, bipolar disorder, and healthy controls (sample size: 531 individuals). PE: phosphatidylethanolamine; DG-SYM: Digit-Symbol test.

Fig. 2. Lipid class-based enrichment analysis in LipidR for different cognitive tests.

Distribution of log fold change (logFC) per lipid class, with significantly enriched classes (marked in red) for mean-based low (as seen in the plots) versus high cognitive tests results in the full dataset with the effect of covariates. TMT-A, Trail-Making Test part A; TMT-B, Trail-Making Test part B; DGT-SP-FRW, Verbal Digit Span forward; DGT-SP-BCK, Verbal Digit Span backward; DG-SYM, Digit-Symbol; MWT-B, Multiple-choice Vocabulary Intelligence.