Phospholipids and insulin resistance in psychosis: a lipidomics study of twin pairs discordant for schizophrenia

Abstract

Background: Several theories have been proposed to conceptualize the pathological processes inherent to schizophrenia. The 'prostaglandin deficiency' hypothesis postulates that defective enzyme systems converting essential fatty acids to prostaglandins lead to diminished levels of prostaglandins, which in turn affect synaptic transmission.

Methods: Here we sought to determine the lipidomic profiles associated with schizophrenia in twin pairs discordant for schizophrenia as well as unaffected twin pairs. The study included serum samples from 19 twin pairs discordant for schizophrenia (mean age 51 ± 10 years; 7 monozygotic pairs; 13 female pairs) and 34 age and gender matched healthy twins as controls. Neurocognitive assessment data and gray matter density measurements taken from high-resolution magnetic resonance images were also obtained. A lipidomics platform using ultra performance liquid chromatography coupled to time-of-flight mass spectrometry was applied for the analysis of serum samples.

Results: In comparison to their healthy co-twins, the patients had elevated triglycerides and were more insulin resistant. They had diminished lysophosphatidylcholine levels, which associated with decreased cognitive speed.

Conclusions: Our findings may be of pathophysiological relevance since lysophosphatidylcholines, byproducts of phospholipase A2-catalyzed phospholipid hydrolysis, are preferred carriers of polyunsaturated fatty acids across the blood-brain barrier. Furthermore, diminishment of lysophosphatidylcholines suggests that subjects at risk of schizophrenia may be more susceptible to infections. Their association with cognitive speed supports the view that altered neurotransmission in schizophrenia may be in part mediated by reactive lipids such as prostaglandins.

Figure 1

Lipid levels across the three study groups, as obtained from the lipidomics platform. (a) Mean lipid levels within each cluster. Error marks show standard error of the mean. The F-test (across the three groups) P-values are shown. (b) Profiles of selected representative abundant lipids from three clusters. lysoPC(16:0) and lysoPC(18:0) are the two most abundant lysophosphatidylcholines measured in plasma. The lipid levels are shown as beanplots [22], which provide information on the mean level (solid line), individual data points (short lines), and the density of the distribution. Note that the concentration scale in beanplots is logarithmic. Tukey all-pair comparison post-hoc test: patients versus co-twins (*P < 0.1, **P < 0.05, ***P < 0.001), patients versus controls (^†P < 0.1, ^††P < 0.05, ^†††P < 0.01). No significant differences were found when comparing co-twins and controls. CoTw, unaffected co-twins; Ctr, controls; Sch, patients.

Figure 2

Dependency network of variables related to schizophrenia. The network was constructed from the selected clinical, lipid cluster, MR image (with selected independent components shown), and neurocognitive assessment data. Node shapes represent different types of variables, node color corresponds to significance and direction of regulation comparing patients versus unaffected co-twins, and line width is proportional to strength of dependency. The cutoff for the presence of edge was set at β = 0.40 by the average non-rejection rate, that is, an edge in the graph was tested positive in 40% of the 500 samplings. The existing edges should be interpreted as direct associations between the pairs of variables. HOMA-IR, Homeostasis Model Assessment index; NS, not significant.

Figure 3

Significant correlations between lipid levels and cortical gray matter density. LysoPC(18:0) level is positively correlated with gray matter density mainly in right precentral gyrus, anterior cingulate areas, and medial parietal and occipital surfaces. The triglyceride cluster LC5 is positively correlated with gray matter density in lateral temporal surfaces on both sides and medial occipital and parietal surfaces on the right side. These results were confirmed using permutation tests.