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

Abstract

BackgroundSeveral 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.MethodsHere 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.ResultsIn 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.ConclusionsOur 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.

Diabetes associated metabolomic perturbations in NOD mice

“…Partial correlations were calculated between the O-PLS-DA identified top 10% feature set and all statistically significant T1D-associated perturbations. This was achieved using reduced order or q-order partial correlations (Castelo and Roverato 2009) (q=1, 19, 38, 56, n=1000), which have been previously implemented for Gaussian graphical models of high-dimensional metabolomic data (Oresic et al 2012). An average non-rejection rate β=0.4 was used as a criteria for accepting pairwise relationships, for which coefficients of partial correlation, p-values and FDR adjusted p-values(Benjamini Y 1995) were calculated.…”

Corruption of the Intra-Gene DNA Methylation Architecture Is a Hallmark of Cancer

“…It has been noted in particular that there is an increase in stochastic methylation variability in regions which are already known to have altered levels of methylation in cancers, leading to aberrant and varying gene expression, and providing an epigenetic mechanism for tumour heterogeneity [8]. It has also been shown recently that statistics based on differential variability of methylation can lead to improved detection of risk markers in pre-cancerous growths [9], [10].…”

“…Previous studies [7], [9], [10] have focussed on the effects of sample to sample variability of methylation; here for the first time, we analyse the association of phenotype with intra-gene variability of methylation. Making use of data derived from the Illumina Infinium HumanMethylation450 platform, which interrogates CpGs genome-wide including with known gene annotations (corresponding to on average 17 CpGs per gene), we have investigated measures of intra-gene methylation architecture, and their ability to differentiate between healthy and disease phenotypes.…”

Application of fatty acid and lipid measurements in neuropsychiatry

“…A study of twins, with one of the twins being schizophrenic, showed that the schizophrenic twin had elevated levels of ether lipids (such as phosphatidylethanolamines and phosphatidylcholines), abundant triglycerides as well as long-chain and PUFA (polyunsaturated fatty acids)-containing triglycerides [46]. However, their healthy twins had higher concentrations of PUFA-containing phosphatidylcholines and phosphatidylethanolamines, lysophosphatidylcholines and short-chain saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA)-containing triglycerides.…”