Association of kynurenine-3-monooxygenase gene with schizophrenia

Neurotoxic products produced during tryptophan metabolism via the kynurenine pathway could be involved in schizophrenia pathogenesis. It has been shown that kynurenine-3-monooxygenase (KMO) is indirectly involved in these products’ formation. KMO polymorphic loci rs2275163 (C/T) and rs1053230 (A/G) were examined in 187 schizophrenia patients and 229 healthy subjects. A genetic combination of allele T and genotype GG was observed more often in a patient group compared with healthy controls (p = 0.003, OR 2.0 (95% CI 1.2–2.9)). In the latter group, this combination was associated with schizophrenia endophenotype (p = 0.04), which manifested in a higher expression of schizotypal personality traits assessed using the MMPI test.     

The p250GAP gene is associated with risk for schizophrenia and schizotypal personality traits

Background

Hypofunction of the glutamate N-Methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. p250GAP is a brain-enriched NMDA receptor-interacting RhoGAP. p250GAP is involved in spine morphology, and spine morphology has been shown to be altered in the post-mortem brains of patients with schizophrenia. Schizotypal personality disorder has a strong familial relationship with schizophrenia. Several susceptibility genes for schizophrenia have been related to schizotypal traits.

Methods

We first investigated the association of eight linkage disequilibrium-tagging single-nucleotide polymorphisms (SNPs) that cover the p250GAP gene with schizophrenia in a Japanese sample of 431 schizophrenia patients and 572 controls. We then investigated the impact of the risk genetic variant in the p250GAP gene on schizotypal personality traits in 180 healthy subjects using the Schizotypal Personality Questionnaire.

Results

We found a significant difference in genotype frequency between the patients and the controls in rs2298599 (χ² = 17.6, p = 0.00015). The minor A/A genotype frequency of rs2298599 was higher in the patients (18%) than in the controls (9%) (χ² = 15.5, p = 0.000083). Moreover, we found that subjects with the rs2298599 risk A/A genotype, compared with G allele carriers, had higher scores of schizotypal traits (F_1,178 = 4.08, p = 0.045), particularly the interpersonal factor (F_1,178 = 5.85, p = 0.017).

Discussion

These results suggest that a genetic variation in the p250GAP gene might increase susceptibility not only for schizophrenia but also for schizotypal personality traits. We concluded that the p250GAP gene might be a new candidate gene for susceptibility to schizophrenia.     

The combined effects of the 5‐ HTTLPR and HTR1A rs6295 polymorphisms modulate decision making in schizophrenia patients

Decision making ability has been reported to be impaired in schizophrenia patients, but no research has examined the genetic bases of this impairment. This study investigated how decision making was affected by the genetic variants in the serotonin transporter gene (triallelic 5‐ HTTLPR) and serotonin receptor 1A gene (rs6295) and their interaction in 465 schizophrenia patients and 448 healthy controls. The Iowa Gambling Task (IGT) was used to evaluate decision making under ambiguity (the first 40 trials) and decision making under risk (the last 60 trials). Results showed that, among the patients, the main effects of 5‐ HTTLPR (F_2,16 = 6.54, P = 0.002) and HTR1A rs6295 (F_2,16 = 3.87, P = 0.021) polymorphisms and their interaction effect (F_4,16 = 3.32, P = 0.005) were significant for the first 40 trials, with the GG genotype of HTR1A rs6295, the L′L′ genotype of 5‐ HTTLPR and the GG‐L′L′ combination showing poorer IGT performance than their counterparts. Results for the healthy controls showed a similar pattern but did not reach statistical significance. No significant effects were found for the last 60 trials. These results are discussed in terms of their implications for our understanding of the genetic mechanisms of decision making in schizophrenia patients as well as healthy adults.     

Polymorphism of RGS2 gene as genetic marker of schizophrenia risk and pharmacogenetic markers of the efficiency of typical neuroleptics

Schizophrenia affects about 1% of the general population. The group of RGS genes that regulate the signaling activity of G protein and modulate signal transduction by the neurotransmitter receptors involved in the pathogenesis of schizophrenia is currently under active investigation. The association of polymorphism in the RGS2 gene with the occurrence of extrapyramidal disorders induced by neuroleptics was demonstrated previously. The present work involved the analysis of DNA from 258 patients with paranoid schizophrenia and 263 healthy blood donors resident in the Republic of Bashkortostan and belonging to Russian and Tatar ethnic groups. Genetic markers of increased risk of paranoid schizophrenia, namely, the genotype RGS2*G/*G (rs2746071) in Russians (p = 0.001, OR = 4.08) and Tatars (p = 0.000; OR = 4.88), the allele RGS2*G (rs2746071) in Russians (p = 0.00003, OR = 2.37) and Tatars (p = 0.000; OR = 2.51), as well as genetic markers associated with reduced disease risk, were identified. Moreover, genetic markers associated with increased risk of neuroleptic parkinsonism in Russian patients with paranoid schizophrenia treated with the typical antipsychotic haloperidol (RGS2*T/*T (rs2746073), RGS2*C/*C (rs4606), and RGS2*A/*A (rs2746071)) and genetic markers of efficient haloperidol therapy in Tatars were identified. The results are consistent with those obtained previously and support the hypothesis concerning the association of RGS2 gene polymorphisms with the risk of extrapyramidal syndrome development during haloperidol therapy and their involvement in the etiology and pathogenesis of schizophrenia.     

Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease

Amyloid beta (Aβ)-mediated synapse dysfunction is an early event in Alzheimer’s disease (AD) pathogenesis and previous studies suggest that NMDA receptor (NMDAR) dysregulation may contribute to these pathological effects. Although Aβ peptides impair NMDAR expression and activity, the mechanisms mediating these alterations in the early stages of AD are unclear. Here, we observed that NMDAR subunit NR2B and PSD-95 levels were aberrantly upregulated and correlated with Aβ₄₂ load in human postsynaptic fractions of the prefrontal cortex in early stages of AD patients, as well as in the hippocampus of 3xTg-AD mice. Importantly, NR2B and PSD95 dysregulation was revealed by an increased expression of both proteins in Aβ-injected mouse hippocampi. In cultured neurons, Aβ oligomers increased the NR2B-containing NMDAR density in neuronal membranes and the NMDA-induced intracellular Ca²⁺ increase, in addition to colocalization in dendrites of NR2B subunit and PSD95. Mechanistically, Aβ oligomers required integrin β1 to promote synaptic location and function of NR2B-containing NMDARs and PSD95 by phosphorylation through classic PKCs. These results provide evidence that Aβ oligomers modify the contribution of NR2B to NMDAR composition and function in the early stages of AD through an integrin β1 and PKC-dependent pathway. These data reveal a novel role of Aβ oligomers in synaptic dysfunction that may be relevant to early-stage AD pathogenesis.Subject terms: Alzheimer''s disease, Extracellular signalling molecules     

Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia

It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.     

A Lead ANRIL Polymorphism Is Associated with Elevated CRP Levels in Periodontitis: A Pilot Case-Control Study

Elevated high sensitive C-reactive protein (hsCRP) is a marker for systemic inflammation and a risk marker for atherosclerotic cardiovascular disease (ACVD), and has also been associated with periodontitis. Inter-individual variation for hsCRP in periodontitis has been shown. ANRIL is the strongest genetic susceptibility locus for both periodontitis and ACVD, and it is speculated that genetic variation in ANRIL may modulate inflammatory processes. Therefore, we explored the possible association between hsCRP plasma levels and a leading ANRIL single nucleotide polymorphism (SNP) in periodontitis patients and controls. 171 healthy subjects with North European descent (115 periodontitis and 56 controls) were included in this case-control study. hsCRP levels were determined and subjects were genotyped for the leading ANRIL SNP rs1333048. In a multivariate analysis, periodontitis, female gender, increasing BMI and homozygosity for the major allele (AA-genotype) of rs1333048 were significantly associated with elevated hsCRP plasma levels (p = 0.012, p = 0.004, p = 0.007 and p = 0.003, respectively). Periodontitis patients with rs1333048 AA-genotype showed higher levels of hsCRP than those carrying the minor C allele (median: 4.5 mg/L vs. 1.6 mg/L, p_adjusted = 0.007). This study is the first to show that, in addition to gender and BMI, also a leading SNP in ANRIL is explanatory for inter-individual variation in hsCRP levels in periodontitis patients of North European descent.     

A longitudinal study of impact and early stance loads during gait following arthroscopic partial meniscectomy

People following arthroscopic partial medial meniscectomy (APM) are at increased risk of developing knee osteoarthritis. High impact loading and peak loading early in the stance phase of gait may play a role in the pathogenesis of knee osteoarthritis. This was a secondary analysis of longitudinal data to investigate loading-related indices at baseline in an APM group (3 months post-surgery) and a healthy control group, and again 2 years later (follow-up). At baseline, 82 participants with medial APM and 38 healthy controls were assessed, with 66 and 23 re-assessed at follow-up, respectively. Outcome measures included: (i) heel strike transient (HST) presence and magnitude, (ii) maximum loading rate, (iii) peak vertical force (F_z) during early stance. At baseline, maximum loading rate was lower in the operated leg (APM) and non-operated leg (non-APM leg) compared to controls (p≤0.03) and peak F_z was lower in the APM leg compared to non-APM leg (p≤0.01). Over 2 years, peak F_z increased in the APM leg compared to the non-APM leg and controls (p≤0.01). Following recent APM, people may adapt their gait to protect the operated knee from excessive loads, as evidenced by a lower maximum loading rate in the APM leg compared to controls, and a reduced peak F_z in the APM leg compared to the non-APM leg. No differences at follow-up may suggest an eventual return to more typical gait. However, the increase in peak F_z in the APM leg may be of concern for long-term joint health given the compromised function of the meniscus.     

Association between ST8SIA2 and the Risk of Schizophrenia and Bipolar I Disorder across Diagnostic Boundaries

Background

Findings from family studies and recent genome-wide association studies have indicated overlap in the risk genes between schizophrenia and bipolar disorder (BD). After finding a linkage between the ST8SIA2 (ST8 alpha-N-acetyl-neuraminide alpha-2, 8-sicalyltransferase 2 gene) locus (15q26) and mixed families with schizophrenia and BD, several studies have reported a significant association between this gene and schizophrenia or BD. We investigated the genetic association between ST8SIA2 and both schizophrenia and BD in the Korean population.

Methods

A total of 582 patients with schizophrenia, 339 patients with BD, and 502 healthy controls were included. Thirty-one tag single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and three other SNPs showing significant associations in previous studies were genotyped. The associations were evaluated by logistic regression analysis using additive, dominant, and recessive genetic models.

Results

Fourteen of 34 SNPs showed a nominally significant association (p < 0.05) with at least one diagnostic group. These association trends were strongest for the schizophrenia and combined schizophrenia and bipolar I disorder (BD-I) groups. The strongest association was observed in rs11637898 for schizophrenia (p = 0.0033) and BD-I (p = 0.0050) under the dominant model. The association between rs11637898 and the combined schizophrenia and BD-I group (p = 0.0006, under the dominant model) remained significant after correcting for multiple testing.

Discussion

We identified a possible role of ST8SIA2 in the common susceptibility of schizophrenia and BD-I. However, no association trend was observed for bipolar II disorder. Further efforts are needed to identify a specific phenotype associated with this gene crossing the current diagnostic categories.     

Association of SLC18A1, TPH1, and RELN gene polymorphisms with risk of paranoid schizophrenia

A biochip was developed to examine the polymorphisms of genes associated with schizophrenia risk, including DISC1, RELN, ZNF804A, PLXNA2, COMT, SLC18A1, CACNA1C, ANK2, TPH1, PLAA, and SNAP-25. Allele and genotype frequencies of the genes were determined in 198 schizophrenics and 192 healthy subjects from Bashkortostan (ethnic Russians and Tatars). The frequencies of allele A (p = 0.007) and genotype AA (p = 0.002) of the rs2270641 A>C polymorphism of SLC18A1 in the patients with paranoid schizophrenia was lower than in the healthy subjects. The frequency of genotype AA of the rs1800532 C>A polymorphism of TPH1 in the schizophrenics was higher than in the healthy subjects (p = 0.036). Compared with the healthy subjects, the ethnic Tatar patients with paranoid schizophrenia had a lower frequency of allele C of the rs7341475 C>T polymorphism of RELN (p = 0.039) and a higher frequency of genotype AA of the rs1800532 C>A polymorphism of TPH1 (p = 0.019, OR = 2.52, CI 1.18-5.38). The frequency of allele C (p = 0.0001) and genotype GC (p = 0.0001) of the rs1327175 G>C polymorphism of PLXNA2 was elevated in the patients with a family history of paranoid schizophrenia. Based on the results, the SLC18A1, TPH1, and RELN polymorphisms were associated with risk of schizophrenia.     

Selenium, Zinc, and Copper Plasma Levels in Patients with Schizophrenia: Relationship with Metabolic Risk Factors

The aim of this study was to determine the plasma selenium (Se), copper (Cu), and zinc (Zn) levels and to evaluate their possible association with metabolic syndrome (MetS) components in patients with schizophrenia. The study group consisted of 60 patients with schizophrenia and 60 sex- and age-matched healthy controls. Anthropometric measurements, blood pressure, and biochemical analysis of fasting blood were performed in all subjects. Patients with schizophrenia had significantly higher plasma Cu concentrations compared with controls (0.97?±?0.31 vs. 0.77?±?0.32 mg/L, p?=?0.001). The plasma Cu concentration showed a positive correlation with plasma glucose and diastolic blood pressure in the patient groups (r _s ?=?0.263, p?<?0.05 and r _s ?=?0.272, p?<?0.05, respectively). The plasma Se level correlated positive with MetS score (r _s ?=?0.385, p?<?0.01), waist circumference (r _s ?=?0.344, p?<?0.05), plasma glucose (r _s ?=?0.319, p?<?0.05), and triglyceride concentrations (r _s ?=?0.462, p?<?0.001) in patients with schizophrenia. Plasma Zn did not correlate with any of the MetS components. These results suggest that alterations in plasma Cu and Se levels in medicated patients with schizophrenia could be associated with metabolic risk factors.     

Investigation of Associations between NR1D1, RORA and RORB Genes and Bipolar Disorder

Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and gene-based association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test gene-gene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6×10−6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0.027), respectively. Gene-based association was significant for RORA gene (P = 0.0007). Our results support for the involvement of RORs genes in the risk of developing BD. Investigation of the functional properties of genes in the circadian pathway may further enhance our understanding about the pathogenesis of bipolar illness.     

Differential Effects of the Catechol-O-Methyltransferase Val158Met Genotype on the Cognitive Function of Schizophrenia Patients and Healthy Japanese Individuals

Background

The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene has been associated with differences in prefrontal cognitive functions in patients with schizophrenia and healthy individuals. Several studies have indicated that the Met allele is associated with better performance on measures of cognitive function. We investigated whether the COMT Val158Met genotype was associated with cognitive function in 149 healthy controls and 118 patients with schizophrenia.

Methods

Cognitive function, including verbal memory, working memory, motor speed, attention, executive function and verbal fluency, was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS-J). We employed a one-way analysis of variance (ANOVA) and a multiple regression analysis to determine the associations between the COMT Val158Met genotype and the BACS-J measurements.

Results

The one-way ANOVA revealed a significant difference in the scores on the Tower of London, a measure of executive function, between the different Val158Met genotypes in the healthy controls (p = 0.023), and a post-hoc analysis showed significant differences between the scores on the Tower of London in the val/val genotype group (18.6 ± 2.4) compared to the other two groups (17.6 ± 2.7 for val/met and 17.1 ± 3.2 for met/met; p = 0.027 and p = 0.024, respectively). Multiple regression analyses revealed that executive function was significantly correlated with the Val158Met genotype (p = 0.003). However, no evidence was found for an effect of the COMT on any cognitive domains of the BACS-J in the patients with schizophrenia.

Conclusion

These data support the hypothesis that the COMT Val158Met genotype maintains an optimal level of dopamine activity. Further studies should be performed that include a larger sample size and include patients on and off medication, as these patients would help to confirm our findings.     

Molecular Determination of Vascular Endothelial Growth Factor,miRNA-423 Gene Abnormalities by Utilizing ARMS-PCR and Their Association with Fetal Hemoglobin Expression in the Patients with Sickle Cell Disease

Recent studies have indicated that microRNA and VEGF are considered to be genetic modifiers and are associated with elevated levels of fetal haemoglobin HbF, and thus they reduce the clinical impact of sickle haemoglobin (HbS) patients. This cross-sectional study was performed on clinical confirmed subjects of SCD cases. miR-423-rs6505162 C>T and VEGF-2578 C>A genotyping was conducted by ARMS-PCR in SCD and healthy controls. A strong clinical significance was reported while comparing the association of miR-423 C>T genotypes between SCD patients and controls (p = 0.031). The microRNA-423 AA genotype was associated with an increased severity of SCD in codominant model with odd ratio (OR = 2.36, 95% CI, (1.15–4.84), p = 0.018) and similarly a significant association was observed in recessive inheritance model for microRNA-423 AA vs (CC+CA) genotypes (OR = 2.19, 95% CI, (1.32–3.62), p < 0.002). The A allele was associated with SCD severity (OR = 1.57, 95% CI, (1.13–2.19), p < 0.007). The distribution of VEGF-2578 C>A genotypes between SCD patients and healthy controls was significant (p < 0.013). Our results indicated that in the codominant model, the VEGF-2578-CA genotype was strongly associated with increased SCD severity with OR = 2.56, 95% CI, (1.36–4.82), p < 0.003. The higher expression of HbA1 (65.9%), HbA2 (4.40%), was reported in SCD patients carrying miR-423-AA genotype than miR-423 CA genotype in SCD patients carrying miR-423 CA genotype HbA1 (59.98%), HbA2 (3.74%) whereas SCD patients carrying miR-423 CA genotype has higher expression of HbF (0.98%) and HbS (38.1%) than in the patients carrying AA genotype HbF (0.60%), HbS (36.1%). ARMS-PCR has been proven to be rapid, inexpensive and is highly applicable to gene mutation screening in laboratories and clinical practices. This research highlights the significance of elucidating genetic determinants that play roles in the amelioration of the HbF levels that is used as an indicator of severity of clinical complications of the monogenic disease. Further well-designed studies with larger sample sizes are necessary to confirm our findings.     

Role of IL-17 Variants in Preeclampsia in Chinese Han Women

Previous studies have suggested an important role for IL-17, mainly secreted by Th17 cells, in the development of systemic inflammation in preeclampsia (PE). This study therefore investigated the association between genetic variants in IL-17A, IL-17F, and IL-17RA and susceptibility to PE in Chinese Han women. We recruited 1,031 PE patients and 1,298 controls of later pregnant women, and used TaqMan allelic discrimination real-time PCR to genotype the polymorphisms of IL17A rs2275913, IL-17F rs763780, and IL-17RA rs4819554. No significant differences in genotypic or allelic frequencies were found at all three polymorphic sites between PE patients and controls (rs2275913: genotype χ² = 0.218, p = 0.897 and allele χ² = 0.157, p = 0.692, OR = 1.024, 95%CI 0.911–1.152; rs763780: genotype χ² = 1.948, p = 0.377 and allele χ² = 1.242, p = 0.265, OR = 0.897, 95%CI 0.741–1.086; rs4819554: genotype χ² = 0.633, p = 0.729 and allele χ² = 0.115, p = 0.735, OR = 1.020, 95%CI 0.908–1.146). There were also no significant differences in genetic distributions between mild/severe PE or early/late-onset PE and control subgroups. Our data indicate that the genetic variants of rs2275913 in IL-17A, rs763780 in IL-17F, and rs4819554 in IL-17RA may not play a role in the pathogenesis of PE in Chinese Han women. However, these findings should be confirmed in other ethnic populations.     

Oxidative damage in Parkinson disease: Measurement using accurate biomarkers

Oxidative damage has been implicated in the pathogenesis of Parkinson disease (PD) but the literature data are confusing. Using products of lipid and DNA oxidation measured by accurate methods, we assessed the extent of oxidative damage in PD patients. The levels of plasma F₂-isoprostanes (F₂-IsoPs), hydroxyeicosatetraenoic acid products (HETEs), cholesterol oxidation products, neuroprostanes (F₄-NPs), phospholipase A₂ (PLA₂) and platelet activating factor–acetylhydrolase (PAF-AH) activities, urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), and serum high-sensitivity C-reactive protein were compared in 61 PD patients and 61 age-matched controls. The levels of plasma F₂-IsoPs, HETEs, 7β-and 27-hydroxycholesterol, 7-ketocholesterol, F₄-NPs, and urinary 8-OHdG were elevated, whereas the levels of plasma PLA₂ and PAF-AH activities were lower, in PD patients compared to controls (p <  0.05). The levels of plasma F₂-IsoPs, HETEs, and urinary 8-OHdG were higher in the early stages of PD (p trend <  0.05). There was a significant negative correlation between the cumulative intake of levodopa and urinary 8-OHdG (r =  ?0.305, p =  0.023) and plasma total HETEs (r =  ?0.285, p =  0.043). Oxidative damage markers are systemically elevated in PD, which may give clues about the relation of oxidative damage to the onset and progression of PD.     

Hippocampal Subfield Volumes in First Episode and Chronic Schizophrenia

BackgroundReduced hippocampal volume in schizophrenia is a well-replicated finding. New imaging techniques allow delineation of hippocampal subfield volumes. Studies including predominantly chronic patients demonstrate differences between subfields in sensitivity to illness, and in associations with clinical features. We carried out a cross-sectional and longitudinal study of first episode, sub-chronic, and chronic patients, using an imaging strategy that allows for the assessment of multiple hippocampal subfields.MethodsHippocampal subfield volumes were measured in 34 patients with schizophrenia (19 first episode, 6 sub-chronic, 9 chronic) and 15 healthy comparison participants. A subset of 10 first episode and 12 healthy participants were rescanned after six months.ResultsTotal left hippocampal volume was smaller in sub-chronic (p = 0.04, effect size 1.12) and chronic (p = 0.009, effect size 1.42) patients compared with healthy volunteers. The CA2-3 subfield volume of chronic patients was significantly decreased (p = 0.009, effect size 1.42) compared to healthy volunteers. The CA4-DG volume was significantly reduced in all three patient groups compared to healthy group (all p < 0.005). The two affected subfield volumes were inversely correlated with severity of negative symptoms (p < 0.05). There was a small, but statistically significant decline in left CA4-DG volume over the first six months of illness (p = 0.01).ConclusionsImaging strategies defining the subfields of the hippocampus may be informative in linking symptoms and structural abnormalities, and in understanding more about progression during the early phases of illness in schizophrenia.     

Genetic variants of GRIA1 are associated with susceptibility to schizophrenia in Korean population

The α-amino-3-hydroxy-5-methyl-4-propionic acid (AMPA) receptors are important for glutamate synaptic transmission in the central nervous system. Glutamate receptor, ionotropic, AMPA receptor 1 gene (GRIA1) belongs to the family of AMPA receptors. There is increasing evidence that AMPA receptors dysfunction may be related to an increased susceptibility to schizophrenia. The aim of this study was therefore to investigate whether genetic polymorphisms of GRIA1 are associated with schizophrenia and their clinical symptoms (hallucinations and delusions) in Korean population. Five single nucleotide polymorphisms (rs1428920, rs1552834, rs1422889, rs10035143, and rs2926835) of the GRIA1 were genotyped in 218 schizophrenia patients and 380 healthy controls, using a direct sequencing. All patients were evaluated by the Operational Criteria Checklist for Psychotic Illness. The genotype and allelic frequencies of rs1428920 and rs2926835 showed significant association between schizophrenia and controls (rs1428920, permutation p?=?0.008, 0.008; rs2926835, permutation p?=?0.038, 0.041, respectively). A significantly increased risk of schizophrenia was associated with the A allele of rs1428920 and rs2926835 of GRIA1. Furthermore, we found that rs1428920 was weakly associated with hallucinations of schizophrenia, but this significance disappeared after multiple testing (permutation p?=?0.119). These results suggest that GRIA1 polymorphism may have influence upon the risk of developing schizophrenia.     

A Preliminary Genetic Analysis of Complement 3 Gene and Schizophrenia

Complement pathway activation was found to occur frequently in schizophrenia, and complement 3 (C3) plays a major role in this process. Previous studies have provided evidence for the possible role of C3 in the development of schizophrenia. In this study, we hypothesized that the gene encoding C3 (C3) may confer susceptibility to schizophrenia in Han Chinese. We analyzed 7 common single nucleotide polymorphisms (SNPs) of C3 in 647 schizophrenia patients and 687 healthy controls. Peripheral C3 mRNA expression level was measured in 23 drug-naïve patients with schizophrenia and 24 controls. Two SNPs (rs1047286 and rs2250656) that deviated from Hardy-Weinberg equilibrium were excluded for further analysis. Among the remaining 5 SNPs, there was no significant difference in allele and genotype frequencies between the patient and control groups. Logistic regression analysis showed no significant SNP-gender interaction in either dominant model or recessive model. There was no significant difference in the level of peripheral C3 expression between the drug-naïve schizophrenia patients and healthy controls. In conclusion, the results of this study do not support C3 as a major genetic susceptibility factor in schizophrenia. Other factors in AP may have critical roles in schizophrenia and be worthy of further investigation.