Identification of a Biological Signature for Schizophrenia in Serum

Institute of Biotechnology, University of Cambridge, Cambridge, UK.
Molecular Psychiatry (Impact Factor: 14.5). 04/2011; 17(5):494-502. DOI: 10.1038/mp.2011.42
Source: PubMed


Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure serum concentrations of 181 proteins and small molecules in 250 first and recent onset SCZ, 35 major depressive disorder (MDD), 32 euthymic bipolar disorder (BPD), 45 Asperger syndrome and 280 control subjects. Preliminary analysis resulted in identification of a signature comprised of 34 analytes in a cohort of closely matched SCZ (n=71) and control (n=59) subjects. Partial least squares discriminant analysis using this signature gave a separation of 60-75% of SCZ subjects from controls across five independent cohorts. The same analysis also gave a separation of ~50% of MDD patients and 10-20% of BPD and Asperger syndrome subjects from controls. These results demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This study lays the groundwork for development of a diagnostic test that can be used as an aid for distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric illnesses with overlapping symptoms.

Download full-text


Available from: Emanuel Schwarz, Oct 01, 2015
62 Reads
  • Source
    • "On the other hand exposure to the non-immunoregulatory crowd infections is common in high-income urban settings. Crowd infections, such as rubella or measles, can cause inflammatory events during pregnancy that lead to fetal CNS developmental abnormalities associated with the subsequent appearance of autism and schizophrenia (extensively reviewed and referenced in Meyer et al., 2011) (Crespi and Thiselton, 2011; Schwarz et al., 2011; Zerbo et al., 2012). In fact, it may be the convergence of a lack of contact with Old Friends, together with exposure to crowd infections that has the most potential for damaging effects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The immune system influences brain development and function. Hygiene and other early childhood influences impact the subsequent function of the immune system during adulthood, with consequences for vulnerability to neurodevelopmental and psychiatric disorders. Inflammatory events during pregnancy can act directly to cause developmental problems in the central nervous system (CNS) that have been implicated in schizophrenia and autism. The immune system also acts indirectly by "farming" the intestinal microbiota, which then influences brain development and function via the multiple pathways that constitute the gut-brain axis. The gut microbiota also regulates the immune system. Regulation of the immune system is crucial because inflammatory states in pregnancy need to be limited, and throughout life inflammation needs to be terminated completely when not required; for example, persistently raised levels of background inflammation during adulthood (in the presence or absence of a clinically apparent inflammatory stimulus) correlate with an increased risk of depression. A number of factors in the perinatal period, notably immigration from rural low-income to rich developed settings, caesarean delivery, breastfeeding and antibiotic abuse have profound effects on the microbiota and on immunoregulation during early life that persist into adulthood. Many aspects of the modern western environment deprive the infant of the immunoregulatory organisms with which humans co-evolved, while encouraging exposure to non-immunoregulatory organisms, associated with more recently evolved "crowd" infections. Finally, there are complex interactions between perinatal psychosocial stressors, the microbiota, and the immune system that have significant additional effects on both physical and psychiatric wellbeing in subsequent adulthood.
    Brain research 04/2014; 1617. DOI:10.1016/j.brainres.2014.04.004 · 2.84 Impact Factor
  • Source
    • "Serum samples from drug-free people with AS (n = 30) and controls (n = 29) were analyzed using the HumanMAP panel comprised of immunoassays for 119 analytes (Additional file 1: Table S1) in a Clinical Laboratory Improved Amendments-certified laboratory at Myriad-RBM (Austin, TX, USA) as described previously [6,11]. The assays were calibrated using duplicate standard curves of each analyte and raw intensity measurements converted to protein concentrations using proprietary software. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The higher prevalence of Asperger Syndrome (AS) and other autism spectrum conditions in males has been known for many years. However, recent multiplex immunoassay profiling studies have shown that males and females with AS have distinct proteomic changes in serum. Here, we analysed sera from adults diagnosed with AS (males = 14, females = 16) and controls (males = 13, females = 16) not on medication at the time of sample collection, using a combination of multiplex immunoassay and shotgun label-free liquid chromatography mass spectrometry (LC-MSE). The main objective was to identify sex-specific serum protein changes associated with AS. Multiplex immunoassay profiling led to identification of 16 proteins that were significantly altered in AS individuals in a sex-specific manner. Three of these proteins were altered in females (ADIPO, IgA, APOA1), seven were changed in males (BMP6, CTGF, ICAM1, IL-12p70, IL-16, TF, TNF-alpha) and six were changed in both sexes but in opposite directions (CHGA, EPO, IL-3, TENA, PAP, SHBG). Shotgun LC-MSE profiling led to identification of 13 serum proteins which had significant sex-specific changes in the AS group and, of these, 12 were altered in females (APOC2, APOE, ARMC3, CLC4K, FETUB, GLCE, MRRP1, PTPA, RN149, TLE1, TRIPB, ZC3HE) and one protein was altered in males (RGPD4). The free androgen index in females with AS showed an increased ratio of 1.63 compared to controls. Taken together, the serum multiplex immunoassay and shotgun LC-MSE profiling results indicate that adult females with AS had alterations in proteins involved mostly in lipid transport and metabolism pathways, while adult males with AS showed changes predominantly in inflammation signalling. These results provide further evidence that the search for biomarkers or novel drug targets in AS may require stratification into male and female subgroups, and could lead to the development of novel targeted treatment approaches.
    Molecular Autism 01/2014; 5(1):4. DOI:10.1186/2040-2392-5-4 · 5.41 Impact Factor
  • Source
    • "The first phase of the study was aimed at detection of serum analytes which were present at significantly different levels in schizophrenia patients compared to controls. This resulted in identification of 41 analytes, 33 of which have identified in previous multiplex immunoassay profiling studies of schizophrenia and control subjects [12], [13], [22], [23]. As described previously, these analytes represented hormonal (cortisol, luteinizing hormone, follicle-stimulating hormone, pancreatic polypeptide, progesterone, resistin, chromogranin A and leptin); growth factor (sortilin, epidermal growth factor, insulin-like growth factor binding protein 2, hepatocyte growth factor); inflammation (macrophage migration inhibitory factor, alpha-2-macroglobulin, haptoglobin, carcinoembryonic antigen, interleukin-8, interleukin-10, complement C3, CD40 ligand, tissue inhibitor of metalloproteinases 1, alpha-1-antitrypsin, RANTES, tumour necrosis factor receptor 2, serum amyloid P and eotaxin); and other (apolipoprotein CIII, apolipoprotein A1, prostatic acid phophatase) pathways. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In schizophrenia, sex specific dimorphisms related to age of onset, course of illness and response to antipsychotic treatment may be mirrored by sex-related differences in the underlying molecular pathways. Here, we have carried out multiplex immunoassay profiling of sera from 4 independent cohorts of first episode antipsychotic naive schizophrenia patients (n = 133) and controls (n = 133) to identify such sex-specific illness processes in the periphery. The concentrations of 16 molecules associated with hormonal, inflammation and growth factor pathways showed significant sex differences in schizophrenia patients compared with controls. In female patients, the inflammation-related analytes alpha-1-antitrypsin, B lymphocyte chemoattractant BLC and interleukin-15 showed negative associations with positive and negative syndrome scale (PANSS) scores. In male patients, the hormones prolactin and testosterone were negatively associated with PANSS ratings. In addition, we investigated molecular changes in a subset of 33 patients before and after 6 weeks of treatment with antipsychotics and found that treatment induced sex-specific changes in the levels of testosterone, serum glutamic oxaloacetic transaminase, follicle stimulating hormone, interleukin-13 and macrophage-derived chemokine. Finally, we evaluated overlapping and distinct biomarkers in the sex-specific molecular signatures in schizophrenia, major depressive disorder and bipolar disorder. We propose that future studies should investigate the common and sex-specific aetiologies of schizophrenia, as the current findings suggest that different therapeutic strategies may be required for male and female patients.
    PLoS ONE 11/2013; 8(11):e78729. DOI:10.1371/journal.pone.0078729 · 3.23 Impact Factor
Show more