MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese

Recently, evidence has accumulated indicating that the MIR137 gene and the target gene CACNA1C of miR-137 might be two of the most robustly implicated genes in schizophrenia. In this study, we examined 33 single nucleotide polymorphisms (SNPs) located in two genes by performing an association analysis in a cohort of 1430 schizophrenia patients and 1570 healthy Han Chinese control subjects. Single SNP association, sex-specific association and haplotype association analyses were performed. For the rs1625579 marker in MIR137 and the rs1006737 and rs4765905 markers in CACNA1C, significant differences in the allele frequencies were found between the patients and controls (p = 0.007949, p = 0.013658 and p = 0.013999, respectively), and the genotype association analysis for them suggested a similar pattern (p = 0.023167, p = 0.046623 and p = 0.047824, respectively). Further analysis of the haplotype rs1006737–rs4765905–rs882194 in CACNA1C showed significant associations with schizophrenia (corrected global p < 0.005), and two haplotypes (ACC and ACT) in the block were significantly increased in the patients. When the samples were analyzed separately by gender, we found no significant sex-specific associations in MIR137 and CACNA1C, which was similar to the results from the relevant haplotype association analysis in the female and male subgroups. We have provided new evidence supporting the association between MIR137 and CACNA1C and schizophrenia in the Han Chinese population.     

Association of calcineurin A gamma subunit (PPP3CC) and early growth response 3 (EGR3) gene polymorphisms with susceptibility to schizophrenia in a Japanese population

To examine the association of PPP3CC (rs10108011 and rs2461491) and EGR3 (rs3750192) single-nucleotide polymorphisms (SNPs) with Japanese schizophrenia, we performed a case–control association study using 337 patients and 369 healthy controls. As a result, by our moderated cohort-size study, PPP3CC and EGR3 are not genetic risk factors for schizophrenia, whereas meta-analysis showed weak association of rs10108011 with schizophrenia in the Japanese population (odds ratio (OR) = 1.12, P = 0.01).     

The lack of association between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms and schizophrenia in a group of Turkish population

IntroductionSchizophrenia is a complex neuropsychiatric disorder with deficits of multiple domains of cognitive functions, volition and emotions. Family and twin studies have provided cumulative evidence for the genetic basis of schizophrenia. The aetiolgy of this disease involves the interplay of multifactiorial inheritance operating on brain maturational processes and polygenic inheritance with some genes showing susceptibility at many genomic locations such as 22q and 11q.The catechol-O-methyltransferase (COMT-22q11) is an extensively studied candidate gene for schizophrenia. COMT acts as an enzymatic detoxicating barrier between the blood and other tissues regulating the amounts of active dopamine and norepinephrine in various parts of the brain and therefore to be associated with schizophrenia.The presence of a common functional single nucleotide polymorphism (SNP) in exon 4 [Guanine (G) Adenine (A); Val108/158Met], alters the enzymatic activity with a trimodal distribution of high-HH, intermediate-HL and low-LL activity alleles which appear to have association with schizophrenia.Brain-derived neurotrophic factor (BDNF-11q13) is a member of the nerve growth factor family working as a molecular regulator of neuronal development and plasticity. Molecules that are critical in the development and survival of neurons such as BDNF play a significant role in the neuropathology of schizophrenia. While upregulation of BDNF increases the neuronal cell size and synaptic plasticity, a functional polymorphism at codon 66 [G→A; Val66Met] down regulates this process and induces schizophrenia.ObjectiveIn the present study, our aim was to investigate the differences in allele frequencies between schizophrenic patients [n = 97 (51 men, 46 women)] and control group [n = 376 (228 men, 148 women)] subjects.ResultsWhen the control and schizophrenia groups were compared for BDNFVal66Met polymorphism, we did not find a significant difference between the study groups either for genotype (χ² = 3.370447, p > 0.05) or Val/Met haplotype analysis (χ² = 2.840264, p > 0.05). When a comparison was revealed for COMT-Val108/158Met polymorphism, no significant difference was detected among schizophrenia and control groups for genotype (χ² = 0.373330, p > 0.05) and Val/Met haplotype analysis (χ² = 0.339073, p > 0.05). When the control and study groups were compared for BDNFVal66Met–COMTVal108/158Met polymorphisms compound genotype and haplotype analyses, there was no significant difference between the two groups (χ² = 11.015; p > 0.05 and χ² = 3.191; p > 0.05), respectively.ConclusionOur results indicate that there is no association between schizophrenia and BDNF–COMT polymorphisms and haplotypes analysis. We also did not find an association between schizophrenia and BDNF–COMT compound genotype and haplotype analyses. Although our study is unique in Turkey as combining BDNF and COMT compound genotype–haplotype analyses, for a generalization of Turkish schizophrenia patient's susceptibility to schizophrenia; we need further studies with an enlarged cohort.     

Association of dopamine gene variants,emotion dysregulation and ADHD in autism spectrum disorder

The aim of the present study was to evaluate the association of dopaminergic gene variants with emotion dysregulation (EMD) and attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD). Three dopamine transporter gene (SLC6A3/DAT1) polymorphisms (intron8 5/6 VNTR, 3′-UTR 9/10 VNTR, rs27072 in the 3′-UTR) and one dopamine D2 receptor gene (DRD2) variant (rs2283265) were selected for genotyping based on à priori evidence of regulatory activity or, in the case of DAT1 9/10 VNTR, commonly reported associations with ADHD. A sample of 110 children with ASD was assessed with a rigorously validated DSM-IV-referenced rating scale. Global EMD severity (parents’ ratings) was associated with DAT1 intron8 (ηp² = .063) and rs2283265 (ηp² = .044). Findings for DAT1 intron8 were also significant for two EMD subscales, generalized anxiety (ηp² = .065) and depression (ηp² = .059), and for DRD2 rs2283265, depression (ηp² = .053). DRD2 rs2283265 was associated with teachers’ global ratings of ADHD (ηp² = .052). DAT1 intron8 was associated with parent-rated hyperactivity (ηp² = .045) and both DAT1 9/10 VNTR (ηp² = .105) and DRD2 rs2283265 (ηp² = .069) were associated with teacher-rated inattention. These findings suggest that dopaminergic gene polymorphisms may modulate EMD and ADHD symptoms in children with ASD but require replication with larger independent samples.     

Further evidence for genetic association of CACNA1C and schizophrenia: New risk loci in a Han Chinese population and a meta-analysis

CACNA1C (12p13.3) has been implicated as a susceptibility gene for schizophrenia by several replicated genome wide association studies. While these results have been consistent among studies in European populations, the findings in East Asian populations have varied. To test whether CACNA1C is a risk gene for schizophrenia, we conducted a case–control study in 5897 schizophrenic patients and 6323 healthy control subjects selected from Han Chinese population. Our study replicated the positive associations of rs1006737 (P = 0.0108, OR = 1.16, 95% CI: 1.03–1.29) and rs1024582 (P = 0.0062, OR = 1.18, 95% CI: 1.05–1.33), and identified a novel risk locus, rs2007044 (P = 0.0053, OR = 1.08, 95% CI: 1.02–1.14). A meta-analysis of rs1006737 combining our study and previous studies was conducted in a total of 8222 schizophrenia cases and 24,661 healthy controls. In the meta-analysis, the association between rs1006737 and schizophrenia remained significant (OR = 1.14, 95% CI: 1.07–1.22, P = 0.0001). Stratified analysis showed no heterogeneity between East Asian and European ancestries (χ²[1] = 0.07, P = 0.795), and the difference in pooled ORs between ancestries was not significant (Z = 0.25, P = 0.801). Our results provide further support for associations of rs1006737 and rs1024582 with schizophrenia, identify a new risk locus rs2007044 in a Han Chinese population, and further establish CACNA1C as an important susceptibility gene for the disease across world populations.     

Association of a polymorphism in the ABCB1 gene with Parkinson's disease

The ATP-binding cassette, sub-family B, member 1 (ABCB1) gene encoding the protein P-glycoprotein (P-gp) has been implicated in the pathophysiology of Parkinson's disease (PD) due to its role in regulating transport of endogenous molecules and exogenous toxins. In the present study, we analyzed the ABCB1 single nucleotide polymorphisms (SNPs) 1236C/T (exon 12), 2677G/T/A (exon 21) and 3435C/T (exon 26) in 288 Swedish PD patients and 313 control subjects and found a significant association of SNP 1236C/T with disease (p = 0.0159; χ² = 8.28), whereas the distributions of wild-type and mutated alleles were similar for 2677G/T/A and 3435C/T in patients and controls. Haplotype analysis revealed significant association of the 1236C–2677G haplotype with PD (p = 0.026; χ² = 4.955) and a trend towards association with disease of the 1236C–2677G–3435C haplotype (p = 0.072; χ² = 3.229). Altered ABCB1 and/or P-pg expression was recently shown in PD patients, and impaired drug efflux across barriers such as the gastrointestinal and nasal mucosal linings or the blood–brain barrier, might result in accumulation of drugs and/or endogenous molecules in toxic amounts, possibly contributing to disease. ABCB1 polymorphisms thus constitute an example of how genetic predisposition and environmental influences may combine to increase risk of PD.     

Association study of IL10, IL1β, and IL1RN and schizophrenia using tag SNPs from a comprehensive database: Suggestive association with rs16944 at IL1β

Genetic association studies of several candidate cytokine genes have been motivated by evidence of immune dysfunction among patients with schizophrenia. Intriguing but inconsistent associations have been reported with polymorphisms of three positional candidate genes, namely IL1β, IL1RN, and IL10. We used comprehensive sequencing data from the Seattle SNPs database to select tag SNPs that represent all common polymorphisms in the Caucasian population at these loci. Associations with 28 tag SNPs were evaluated in 478 cases and 501 unscreened control individuals, while accounting for population sub-structure using the genomic control method. The samples were also stratified by gender, diagnostic category, and exposure to infectious agents. Significant association was not detected after correcting for multiple comparisons. However, meta-analysis of our data combined with previously published association studies of rs16944 (IL1β − 511) suggests that the C allele confers modest risk for schizophrenia among individuals reporting Caucasian ancestry, but not Asians (Caucasians, n = 819 cases, 1292 controls; p = 0.0013, OR = 1.24, 95% CI 1.09, 1.41).     

Adiposity is increased among high-functioning,non-ambulatory patients with spinal muscular atrophy

The relationship between body composition and function in spinal muscular atrophy (SMA) is poorly understood. 53 subjects with SMA were stratified by type and Hammersmith functional motor scale, expanded score into three cohorts: low-functioning non-ambulatory (type 2 with Hammersmith score <12, n = 19), high-functioning non-ambulatory (type 2 with Hammersmith score ⩾ 12 or non-ambulatory type 3, n = 17), and Ambulatory (n = 17). Lean and fat mass was estimated using dual-energy X-ray absorptiometry. Anthropometric data was incorporated to measure fat-free (lean mass in kg/stature in m²) and fat (fat mass in kg/stature in m²) mass indices, the latter compared to published age and sex norms. Feeding dysfunction among type 2 subjects was assessed by questionnaire. Fat mass index was increased in the high-functioning non-ambulatory cohort (10.4 ± 4.5) compared with both the ambulatory (7.2 ± 2.1, P = 0.013) and low-functioning non-ambulatory (7.6 ± 3.1, P = 0.040) cohorts. 12 of 17 subjects (71%) in the high-functioning non-ambulatory cohort had fat mass index >85th percentile for age and gender (connoting “at risk of overweight”) versus 9 of 19 subjects (47%) in the low-functioning non-ambulatory cohort and 8 of 17 ambulatory subjects (47%). Despite differences in clinical function, a similar proportion of low functioning (7/18, 39%) and high functioning (2/7, 29%) type 2 subjects reported swallowing or feeding dysfunction. Non-ambulatory patients with relatively high clinical function may be at particular risk of excess adiposity, perhaps reflecting access to excess calories despite relative immobility, emphasizing the importance of individualized nutritional management in SMA.     

Pretreatment levels of the fatty acid handling proteins H-FABP and CD36 predict response to olanzapine in recent-onset schizophrenia patients

Traditional schizophrenia pharmacotherapy remains a subjective trial and error process involving administration, titration and switching of drugs multiple times until an adequate response is achieved. Despite this time-consuming and costly process, not all patients show an adequate response to treatment. As a consequence, relapse is a common occurrence and early intervention is hampered. Here, we have attempted to identify candidate blood biomarkers associated with drug response in 121 initially antipsychotic-free recent-onset schizophrenia patients treated with widely-used antipsychotics, namely olanzapine (n = 40), quetiapine (n = 23), risperidone (n = 30) and a mixture of these drugs (n = 28). Patients were recruited and investigated as two separate cohorts to allow biomarker validation. Data analysis showed the most significant relationship between pre-treatment levels of heart-type fatty acid binding protein (H-FABP) and response to olanzapine (p = 0.008, F = 8.6, β = 70.4 in the discovery cohort and p = 0.003, F = 15.2, β = 24.4 in the validation cohort, adjusted for relevant confounding variables). In a functional follow-up analysis of this finding, we tested an independent cohort of 10 patients treated with olanzapine and found that baseline levels of plasma H-FABP and expression of the binding partner for H-FABP, fatty acid translocase (CD36), on monocytes predicted the reduction of psychotic symptoms (p = 0.040, F = 6.0, β = 116.3 and p = 0.012, F = 11.9, β = −0.0054, respectively). We also identified a set of serum molecules changed after treatment with antipsychotic medication, in particular olanzapine. These molecules are predominantly involved in cellular development and metabolism. Taken together, our findings suggest an association between biomarkers involved in fatty acid metabolism and response to olanzapine, while other proteins may serve as surrogate markers associated with drug efficacy and side effects.     

Prefrontal cortex volume deficit in schizophrenia: A new look using 3 T MRI with manual parcellation

In this study we use high resolution Magnetic Resonance imaging (MRI) and apply rigorous manual tracing criteria in order to assess volumetrically the prefrontal cortex (PFC) in schizophrenia. Previous MRI studies suggested PFC is included in neural systems necessary for emotional processing and cognition, and regional PFC abnormalities might, thus, lead to specific negative symptoms, as well as a frequent association of poorer performance in category switching. The aim of this study was to use 3 T imaging and reliable manual parcellation to determine if, as hypothesized, this higher precision would reveal additional MRI abnormalities in PFC in schizophrenia, and an association between PFC abnormalities and specific negative symptoms, as well as in category switching. Using 3-T MRI, 27 schizophrenia patients and 27 healthy controls were examined. PFC was manually parcellated into frontal pole, superior frontal gyrus (SFG), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG). Left SFG (p = 0.004), bilateral MFG (left: p = 0.007; right: p = 0.007), and bilateral IFG (left: p < 0.001; right: p = 0.002) showed volume reduction. There were symptom associations between smaller left MFG volumes and more affective flattening (R = − 0.465, p = 0.015), and smaller left IFG volumes and poorer performance on the alternating semantic category test (R = 0.440, p = 0.025). In summary, 3-T imaging revealed widespread gyral volume deficits in PFC gyri, and specific associations with selective negative symptoms, such as affective flattening, and with deficits in cognitive switching.     

A polymorphism in CCR1/CCR3 is associated with narcolepsy

Etiology of narcolepsy–cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples.An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P = 1.6 × 10⁻⁵, odds ratio [OR] = 1.86). This rs3181077 association was replicated with the independent sample set (P = 0.032, OR = 1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand.CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function.     

rs2070424 of the SOD1 gene is associated with risk of Alzheimer's disease

ObjectiveOxidative stress plays an important role in Alzheimer's disease (AD) etiopathogenesis. There were several studies that showed impaired antioxidant defense system (ADS) enzymes expression or activity in AD patients. There are only few studies evaluating the importance of ADS gene single nucleotide polymorphisms (SNPs) as risk factors of AD. We evaluated association between chosen SNPs of the enzymes of the ADS and risk of AD.MethodsWe included 400 AD patients and 402 healthy controls. We studied rs1041740, rs4998557 and rs2070424 of the SOD1 gene, rs2855116, rs5746136 and rs4880 of the SOD2 gene and rs3448, rs1050450 and rs1800668 of the GPx-1 gene (real time PCR). To determine the APOE gene common polymorphism, two single-nucleotide polymorphisms (SNPs; NCBI SNPs rs429358 and rs7412) were genotyped (TaqMan assays, Applied Biosystems [ABI], Foster City, CA, USA). The genotype and gender frequencies were compared between the studied groups by the χ² test and mean age by the t-Student test.ResultsAmong all studied SNPs only rs2070424 of the SOD1 gene was a protective factor for AD in an additive (OR = 0.47; 95% CI = 0.30–0.74, p = 0.001) and recessive (OR = 0.47; 95% CI = 0.30–0.75, p = 0.002) models including age, gender and APOE gene status.Conclusionsrs2070424 polymorphism of the SOD1 gene is a risk factor for AD in Polish population. Allel G and genotype AG and GG are protective factors for AD.     

Cortical serotonin7, 1D and 1F receptors: Effects of schizophrenia,suicide and antipsychotic drug treatment

Abnormalities in serotonergic function are thought to be important in the pathology of schizophrenia. Postmortem CNS studies suggest that levels of serotonin receptors may be altered in the cortex of subjects with schizophrenia. Seeking to expand this hypothesis we have examined the effect of schizophrenia and antipsychotic drug treatments on the levels of cortical serotonin₇, _1D and _1F receptors. There was a significant decrease in the binding of [³H]SB 269970 to the serotonin₇ receptor in Brodmann's area 9 from subjects with schizophrenia compared to controls (Mean ± S.E.M.: 8.3 ± 0.76 vs. 11.0 ± 0.64 fmol/mg ETE; p < 0.05) and an increase in the binding of that radioligand in the cortex of rats treated with haloperidol (p = 0.03). There were no significant differences in [³H]sumatriptan binding to the serotonin_1D or serotonin_1F receptor in Brodmann's area 9 from subjects with schizophrenia. There was a significant increase in [³H]sumatriptan binding to the serotonin_1D in binding Layer 2 from subjects who had potentially died by suicide that was not present in other binding layers or for the serotonin_1F or serotonin₇ receptors. There was decrease in [³H]sumatriptan binding to the serotonin_1D, but not serotonin_1F, receptors across all cortical binding layers in rats treated with haloperidol. These data would be consistent with the hypothesis that decreased levels of serotonin₇ receptors in Brodmann's area 9 may be involved in the pathological processes of schizophrenia and that levels of cortical serotonin₇ and _1D receptors can be affected by antipsychotic drug treatment.     

The rs522616 polymorphism in the matrix metalloproteinase-3 (MMP-3) gene is associated with sporadic brain arteriovenous malformation in a Chinese population

In this study, we investigated the association between common variants in the matrix metalloproteinase-3 (MMP-3) gene and the risk of developing sporadic brain arteriovenous malformation (BAVM). We performed genotyping analyses for five single nucleotide polymorphisms (SNPs) in MMP-3 in a case-control study involving 319 Chinese patients with BAVM and 333 Chinese controls. The association between MMP-3 genotypes and the risk of developing BAVM was evaluated using logistic regression analyses. We found that the genotype frequencies were significantly different between patients and controls for the rs522616 A > G variant of MMP-3 (p = 0.02). Logistic regression analysis revealed that the variant genotype of this polymorphism was associated with a significantly decreased risk of BAVM (adjusted odds ratio = 0.62, 95% confidence interval = 0.44–0.87, p = 0.006 for the AG compared with the AA genotype; adjusted odds ratio = 0.68, 95% confidence interval = 0.49–0.94, p = 0.019 for the AG + GG compared with the AA genotype). These findings indicate for the first time that the MMP-3 rs522616 polymorphism may contribute to the etiology of sporadic BAVM in the Chinese population.     

COMT Val158Met polymorphism is related with interpersonal problem solving in schizophrenia

ObjectiveThe aim of this study was to investigate associations between COMT Val¹⁵⁸Met polymorphism, and interpersonal problem solving capacity and cognitive functions in schizophrenia.MethodsCOMT Val¹⁵⁸Met polymorphism was studied with ARMS-PCR method in 99 outpatients with schizophrenia. Brief Psychiatric Rating Scale was used to assess symptom severity. The Assessment of Interpersonal Problem Solving Skills (AIPSS) was used to evaluate problem solving capacity. Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST), were used to measure cognition.ResultsPatients with Met/Met genotype had higher AIPSS subscores for detecting the problem, than those with Val/Val at baseline (p = 0.02). Met allele was also found to be related with higher AIPSS-receiving skills (p = 0.04). Val allele was found to be related with more commission errors in CPT (p = 0.03). There was no relation between Val¹⁵⁸Met polymorphism and WCST and clinical measurements.ConclusionOur findings suggest that Val allele might be related to poor performance on detecting the interpersonal problems, and attention in schizophrenia.     

Acute CSF interleukin-6 trajectories after TBI: Associations with neuroinflammation,polytrauma, and outcome

Traumatic brain injury (TBI) results in a significant inflammatory burden that perpetuates the production of inflammatory mediators and biomarkers. Interleukin-6 (IL-6) is a pro-inflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. We hypothesized that cohort heterogeneity, temporal inflammatory profiles, and concurrent inflammatory marker associations are critical to characterize when targeting subpopulations for anti-inflammatory therapies. Toward this objective, we used serial cerebrospinal fluid (CSF) samples to generate temporal acute IL-6 trajectory (TRAJ) profiles in a prospective cohort of adults with severe TBI (n = 114). We examined the impact of injury type on IL-6 profiles, and how IL-6 profiles impact sub-acute (2 weeks–3 months) serum inflammatory marker load and long-term global outcome 6–12 months post-injury. There were two distinct acute CSF IL-6 profiles, a high and low TRAJ group. Individuals in the high TRAJ had increased odds of unfavorable Glasgow Outcome Scale (GOS) scores at 6 months (adjusted OR = 3.436, 95% CI: 1.259, 9.380). Individuals in the high TRAJ also had higher mean acute CSF inflammatory load compared to individuals in the low TRAJ (p ⩽ 0.05). The two groups did not differ with respect acute serum profiles; however, individuals in the high CSF IL-6 TRAJ also had higher mean sub-acute serum IL-1β and IL-6 levels compared with the low TRAJ group (p ⩽ 0.05). Lastly, injury type (isolated TBI vs. TBI + polytrauma) was associated with IL-6 TRAJ group (χ² = 5.31, p = 0.02). Specifically, there was 70% concordance between those with TBI + polytrauma and the low TRAJ; in contrast, isolated TBI was similarly distributed between TRAJ groups. These data provide evidence that sustained, elevated levels of CSF IL-6 are associated with an increased inflammatory load, and these increases are associated with increased odds for unfavorable global outcomes in the first year following TBI. Future studies should explore additional factors contributing to IL-6 elevations, and therapies to mitigate its detrimental effects on outcome.     

The -141C Ins/Del and Taq1A polymorphism in the dopamine D2 receptor gene may confer susceptibility to schizophrenia in Asian populations

It has been reported that two single nucleotide polymorphisms (SNP) Taq1A and -141C Ins/Del in the DRD2 gene may be associated with susceptibility to schizophrenia. Due to inconclusive and mixed results, a meta-analysis was conducted to further clarify the relationship between the two SNP and schizophrenia susceptibility. A systematic literature search for the association of these two SNP with schizophrenia susceptibility was conducted using PubMed, ScienceDirect, Chinese Biomedical Literature Database, and Chinese National Knowledge Infrastructure. Odds ratios (OR) with 95% confidence intervals (CI) were used to assess the strength of the associations reported. A total of 5558 schizophrenic patients and 6792 healthy controls from 31 articles were included in this study. Evidence regarding the association between -141C Ins/Del polymorphism and schizophrenia was found in the allele frequency comparison (Ins versus Del: OR 1.29, 95% CI 1.06–1.57; p = 0.01, P_raw = 0.1, P_{False Discovery Rate} = 0.023). In ethnic subgroup analysis, the result revealed that the 141C Ins/Del polymorphism was associated with schizophrenia in all genetic models in Asians, but not in Caucasians. For Taq1A polymorphism, a significant association was found in the allele frequency (A1 versus A2: OR 0.71, 95% CI 0.52–0.98, p = 0.03). Stratification by ethnicity indicated an association between the Taq1A polymorphism and schizophrenia in Asians, but not Caucasians. The present study suggests that the -141C Ins/Del polymorphism carries a significantly increased risk of schizophrenia, while the Taq1A polymorphism carries a significantly decreased risk of schizophrenia susceptibility in Asians.     

CYP46A1 variants influence Alzheimer's disease risk and brain cholesterol metabolism

BackgroundCholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer's disease (AD) and results are contradictory.MethodsWe performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.ResultsTwo of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).ConclusionOur results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.     

Auditory P300 latency prolongation with age in schizophrenia: Gender and subcomponent effects

Previous studies showing prolongation of auditory P300b latency with increasing age provided support for post-onset progressive change in schizophrenia. We sought to extend the findings by evaluating the effects of gender and the subcomponents (P3b versus P3a) in schizophrenia (N = 108) and controls (N = 70). P3b latency significantly correlated with age in schizophrenia (Spearman's rho = 0.214, P = 0.026) and in male patients with schizophrenia (rho = 0.260, P = 0.049) whereas, it did not reach significance in female patients with schizophrenia (rho = 0.174, P = 0.23). P3a latency showed no correlation. Our findings may provide evidence for progressive change in the brain function in schizophrenia, and this change may be slower in female than male patients. P3b may serve as a more sensitive index for cognitive decline than P3a.