Analysis of an association between the COMT polymorphism and clinical symptomatology in schizophrenia

Based on their metabolic inactivation of dopamine and norepinephrine, genes encoding the catechol-O-methyltransferase (COMT) enzyme are appropriate candidates to consider in the pathogenesis of schizophrenia. COMT enzyme activity is regulated by a common polymorphism causing substantial variations in enzymatic activity, and evidence for allelic or genotypic association with cognitive and behavioral features of schizophrenia has been noted. Since the role of COMT in schizophrenia remains inconclusive, we determined whether any association exists between COMT genotypes and clinical symptomatology in a large cohort of schizophrenia subjects. DNA was extracted from peripheral blood in 111 patients with DSM-IV criteria schizophrenia (77 M, 34 F) and genotyped for COMT polymorphisms. Subjects were also were rated by means of the PANSS and the CGI. No association was found between COMT genotype or allele frequency and gender. No associations were observed between COMT and CGI or PANSS scores. Our findings do not support hypotheses regarding associations between COMT polymorphisms and clinical state in schizophrenia, contrary to other studies suggesting involvement of the COMT polymorphism with schizophrenia phenotype. Thus, while speculative, it may be suggested that a modifying gene may be required in order for the COMT polymorphism to manifest at the clinical level in schizophrenia with one set of susceptibility genes being more sensitive to COMT enzyme variability than others.     

BDNF gene variants and brain morphology in schizophrenia.

The objective was to investigate putative associations between brain-derived neurotrophic factor gene (BDNF) polymorphisms and brain morphology in patients with schizophrenia and healthy control subjects. Four BDNF polymorphisms were genotyped and analyzed versus 39 brain volume measures in 96 patients with schizophrenia or schizoaffective disorder and 104 healthy subjects. In all subjects, quantitative data on segmented gray, white, and cerebrospinal fluid (CSF) tissue class volumes of total brain and major cerebral lobes including ventricular CSF were obtained using magnetic resonance imaging (MRI). In a randomly selected subset of this population (n = 101-122), MR volumes from cerebellar tonsil, hemispheres, and vermis subregions, striatal structures, hippocampus, and corpus callosum were also measured. The BDNF 11757 G/C polymorphism was highly significantly associated with frontal gray matter volume variation in patients alone and in patients and control subjects combined. In patients only, the 270 C/T polymorphism was associated with total caudate volume. Significant associations were demonstrated between the BDNF 11757 G/C and Val66Met polymorphisms and a global haplotype estimate of four BDNF polymorphisms and the posterior superior cerebellar vermis volume in the controls as well as in the combined group, but not in the patients. The 11757 G/C polymorphism was associated with cerebellar hemisphere white and gray matter volumes in the combined group. The BDNF -633 T/A polymorphism was associated with gray matter of the putamen in the controls. Trends for associations between several polymorphisms/haplotype estimates and MRI volumes were found. BDNF gene variation may influence brain morphology. The effects may be different in patients with schizophrenia and healthy subjects.     

Comparative study of regional homogeneity in schizophrenia and major depressive disorder

Compelling evidence suggests that there is a considerable overlap in structural and functional alternation in the brain between different neuropsychiatric disorders. However, whether these overlaps are specific for schizophrenia has yet to be investigated. A total of 36 patients with paranoid schizophrenia, 43 patients with major depressive disorder (MDD), and 44 healthy controls were recruited to undergo resting‐state functional magnetic resonance imaging (rs‐fMRI) for analysis of regional homogeneity (ReHo). Twelve regions of interest (ROIs) in the frontal and temporal lobes were generated and one‐way ANOVA was performed to test the ReHo differences within these ROIs between the above three groups. The ReHo values within ROIs were extracted to investigate whether a left‐right asymmetry existed in a mental disorder. One‐way ANOVA showed significant differences in ReHo in the right superior frontal gyrus and left superior temporal gyrus; post hoc analysis revealed that schizophrenic patients had lower ReHo in the left superior temporal gyrus than either control subjects or patients with MDD. Increased ReHo was observed in the right superior frontal gyrus in schizophrenic patients compared with control subjects, and a left‐less‐than‐right asymmetry was also found in this region in schizophrenic patients. The above alterations in ReHo were not affected by age and genders. Our study suggests that the altered ReHo in the superior frontal and temporal gyrus may be specific for schizophrenia rather than MDD. A left‐less‐than‐right asymmetry activation pattern may exist in the resting‐state superior frontal gyrus in schizophrenia. This finding would be helpful for better understanding the pathological mechanisms of schizophrenia. © 2012 Wiley Periodicals, Inc.     

The Cys allele (the Ser311Cys polymorphism) of the dopamine d2 receptor is associated with schizophrenia and impairments to selective attention in patients

We report here our studies of the Ser311Cys polymorphism of the D2 dopamine receptor gene in 366 patients with schizophrenia and 387 control subjects. The incidence of the Cys allele was found to be greater (p < 0.009) among patients than controls (8.5% and 3.9%, respectively). Selective attention was also studied on the basis of assessment of parameters of the P300 wave of auditory evoked potentials in 66 patients with different genotypes – SerSer and SerCys (the CysCys genotype was not seen among the patients). This revealed a significant influence of genotype (p = 0.01) on the latent period (LP) of the P300 wave in the frontal, central and temporal leads. In carriers of the Cys allele, which is associated with the risk of developing schizophrenia, LP was longer than in subjects with other genotypes, which is evidence for slowing of mental processes associated with activation of attention resources in these subjects. Thus, the results obtained here support data obtained previously for other populations showing that the Cys allele is associated with schizophrenia, and we also observed an association between this allele and degradation of selective attention in patients.     

Variations in the FTO gene are associated with severe obesity in the Japanese

Variations in the fat-mass and obesity-associated gene (FTO) are associated with the obesity phenotype in many Caucasian populations. This association with the obesity phenotype is not clear in the Japanese. To investigate the relationship between the FTO gene and obesity in the Japanese, we genotyped single nucleotide polymorphisms (SNPs) in the FTO genes from severely obese subjects [n = 927, body mass index (BMI) > or = 30 kg/m2] and normal-weight control subjects (n = 1,527, BMI < 25 kg/m2). A case-control association analysis revealed that 15 SNPs, including rs9939609 and rs1121980, in a linkage disequilibrium (LD) block of approximately 50 kb demonstrated significant associations with obesity; rs1558902 was most significantly associated with obesity. P value in additive mode was 0.0000041, and odds ratio (OR) adjusted for age and gender was 1.41 [95% confidential interval (CI) = 1.22-1.62]. Obesity-associated phenotypes, which include the level of plasma glucose, hemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and blood pressure were not associated with the rs1558902 genotype. Thus, the SNPs in the FTO gene were found to be associated with obesity, i.e., severe obesity, in the Japanese.     

RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity

Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia.     

Effect of Serotonin-Related Gene Polymorphisms on Pathogenesis and Treatment Response in Korean Schizophrenic Patients

Serotonin has been implicated in the pathophysiology of several psychiatric disorders including schizophrenia. Serotonergic system-related genes may be good candidates in investigating the genetic basis of schizophrenia. We aimed to investigate the associations of HTR1A C–1019G, HTR2A–1438A/G, TPH1 218A/C, and TPH2–703G/T variants with schizophrenia. A total of 202 patients with schizophrenia and 165 normal controls were genotyped for HTR1A C–1019G, HTR2A–1438A/G, TPH1 218A/C, and TPH2–703G/T single nucleotide polymorphisms (SNPs). In order to assess the severity of a patient’s psychiatric symptoms, the brief psychiatric rating scale (BPRS), the positive and negative symptom scale (PANSS), and the Calgary depression scale for Schizophrenia (CDSS) were administered. Genotype and allele frequencies were compared between groups via χ² statistics. Associations between the genotypes of candidate SNPs with the severity of symptoms were examined with ANOVA by comparing the mean scores of BPRS, PANSS, and CDSS according to genotype. No significant differences in the genotype distributions and allele frequencies of four SNPs were found between patients with schizophrenia and normal controls. There was a trend towards association of HTR1A C–1019G polymorphism with negative symptom. Negative symptom score of PANSS was lower in the patients with CC genotype than in the G allele carriers. These results suggested that C allele might be associated with lesser negative symptom. More studies are needed to confirm these findings. In the future, we plan to study the associations between schizophrenia and other genetic polymorphisms.     

Association of TNF-alpha polymorphisms in Crohn disease

Clinical and molecular studies implicate tumor necrosis factor alpha (TNF-alpha) as a key mediator in the initiation and propagation of Crohn disease (CD). Genetic associations have been documented between promoter polymorphisms of TNF-alpha and CD; however, these associations have not been universally replicated. In this study, we set out to examine the association of five promoter TNF-alpha polymorphisms in CD subjects from a founder population. In total, 128 CD subjects and 103 ethnically matched healthy controls were genotyped with time-of-flight mass spectrometry for the following five single nucleotide polymorphisms (SNPs) in the 5' flanking region of TNF-alpha gene: -1031 (T-->C), -863 (C-->A), -857 (C-->T), -308 (G-->A), and -238 (G-->A). Primer sequences, termination mixes, and multiplexing were determined with Sequenom SpectroDESIGNER software v1.3.4. The minor allele frequency for the TNF-alpha SNPs in subjects with CD and healthy controls, respectively, were -238 (5.5% vs. 5.3%); -308 (17.6% vs. 18.9%); -857 (5.1% vs. 7.8%); -863 (19.1% vs. 17.5%), and -1031 (24.6% vs. 22.8%). Thus, none of the TNF-alpha variants was associated with CD. Furthermore, no genotype/phenotype correlations were observed for the mutant allele of the TNF-alpha variants and selected clinical outcomes. In conclusion, there was no significant association for any of the TNF-alpha promoter polymorphism tested and CD in the Newfoundland population.     

Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene (GRM8) with schizophrenia.

The glutamatergic dysfunction has been implicated in pathophysiology of schizophrenia. The Group III metabotropic glutamate receptor 4 (mGluR4), 6, 7, and 8 are thought to modulate glutamatergic transmission in the brain by inhibiting glutamate release at the synapse. We tested association of schizophrenia with GRM8 using 22 single nucleofide polymorphisms (SNPs) with the average intervals of 40.3 kb in the GRM8 region in 100 case-control pairs for the SNPs. Although we observed significant associations of schizophrenia with two SNPs, SNP18 (rs2237748, allele: P = 0.0279; genotype: P = 0.0124) and SNP19 (rs2299472, allele: P = 0.0302; genotype: P = 0.0127), none of two SNPs showed significant association with disease after Bonferroni correction. Both SNP18 and SNP19 were included in a large region (>330 kb) in which SNPs are in linkage disequilibrium (LD) at the 3' region of GRM8. We also tested haplotype association of schizophrenia with constructed haplotypes of the SNPs in LD. Significant associations were detected for the combinations of SNP5-SNP6 (chi(2) = 18.12, df = 3, P = 0.0004, P corr = 0.0924 with Bonferroni correction), SNP4-SNP5-SNP6 (chi(2) = 27.50, df = 7, P = 0.0075, P corr = 0.015 with Bonferroni correction), and SNP5-SNP6-SNP7 (chi(2) = 23.92, df = 7, P = 0.0011, P corr = 0.0022 with Bonferroni correction). Thus, we conclude that at least one susceptibility locus for schizophrenia is located within the GRM8 region in Japanese.     

网状内皮素4受体基因多态性与中国汉族精神分裂症关联分析

目的:分析网状内皮素4受体(RTN4R)基因上的5个单核苷酸多态性(SNP)与中国汉族精神分裂症关联,探讨RTN4R基因单核苷酸多态性与精神分裂症易感性的关系。方法:收集符合美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)诊断的528名偏执型精神分裂症患者,在同一地域招募健康体检者528名作为对照,并采用阳性与阴性症状量表(PANSS)评估234例首次发病患者的临床症状,采用基因分型芯片对RTN4R基因上的5个功能单核苷酸多态性位点进行基因分型,分析多态性与疾病的关联性,以及PANSS因子分与RTN4R多态性的关联。结果:成功检测5个单核苷酸多态性位点的基因型,关联分析显示这些位点基因型和等位基因频率分布病例和对照之间差异无统计学意义。与携带rs696880位点GG基因型患者相比,携带AA基因型患者PANSS阳性分[(23.5±5.6)vs.(25.1±7.6),P0.05]、一般精神病理症状分[(42.6±9.9)vs.(46.0±13.4),P0.05]均较低,携带AA基因型患者发病年龄晚于携带GG型患者[(24.9±8.1)岁vs.(22.2±6.2)岁,P0.05]。结论:在中国汉族人群中,RTN4R基因多态性与精神分裂症可能不存在关联,但可能影响疾病表现。     

Evidence for a dysfunctional retrosplenial cortex in patients with schizophrenia: a functional magnetic resonance imaging study with a semantic-perceptual contrast

We investigated whether the retrosplenial and the posterior cingulate cortex (RS-PCC) is functionally impaired in schizophrenia patients. Therefore, we measured functional magnetic resonance imaging (fMRI) signal changes associated with a synonym-judgment task known to activate, among other areas, the RS-PCC. Compared to 12 matched control subjects, 12 schizophrenia patients exhibited reliably weaker activations in the RS-PCC, the dorsolateral prefrontal cortex and the left orbitofrontal cortex (P < 0.05, corrected). Differences in frontal activations are in line with previous studies showing a structurally and functionally affected prefrontal cortex in schizophrenia. The impaired RS-PCC functionality in a semantic task may relate to verbal memory deficits frequently observed in schizophrenia patients, because this region is pivotal for gating information into the medial temporal lobe memory system.     

The COMT val158met polymorphism and brain morphometry in healthy young adults

Catechol-O-methyltransferase (COMT) is the most important mechanism for dopamine degradation in the prefrontal cortex and contains a functional polymorphism (val(158)met) influencing enzyme activity. The low-activity met allele has been associated with better performance on cognitive tasks relying on the prefrontal cortex. Whether COMT also affects brain structure, is still unclear. This study investigated the relationship between the COMT val(158)met polymorphism and brain anatomy in healthy young adults. In a cross-sectional study, structural MRI data and DNA for COMT genotyping were obtained from 154 healthy young adults. Statistical Parametric Mapping software (SPM2) and optimized voxel-based morphometry were used to determine total and regional gray and white matter density differences between genotype groups, as well as age-related gray and white matter density differences within the genotype groups. We found a significant effect of COMT genotype on age-related differences in gray and white matter density in females but not in males. In female val carriers increased gray matter in the temporal and parietal lobe and the cerebellum and increased white matter in the frontal lobes were positively correlated with age; in female met homozygotes decreased gray matter density in the parietal lobe and decreased white matter density in the frontal lobes, the parahippocampal gyrus and the corpus callosum were positively correlated with age. These results suggest that the COMT val(158)met polymorphism may affect age-related differences in gray and white matter density in females.     

Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons

Magnetic resonance imaging was used to investigate the relation between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and volumetric measurements for the medial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) and prefrontal sub-regions (the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, ventral medial prefrontal cortex, orbitofrontal cortex, and straight gyrus) in a Japanese sample of 33 schizophrenia patients and 29 healthy subjects. For the controls, the Met carriers had significantly smaller parahippocampal and left superior frontal gyri than the Val homozygotes. The schizophrenia patients carrying the Met allele had a significantly smaller right parahippocampal gyrus than those with the Val/Val genotype, but the genotype did not affect the prefrontal regions in schizophrenia patients. These findings might reflect different genotypic effects of BDNF on brain morphology in schizophrenia patients and healthy controls, implicating the possible role of the brain morphology as an endophenotype for future genetic studies in schizophrenia.     

Association of DRD2 gene variant with schizophrenia

Schizophrenia is a complex multifactorial disorder for which the pathobiology still remains elusive. Dysfunction of the dopamine D2 receptor signaling has been associated with the illness, but numerous studies provide confounding results. This study investigates the association of synonymous polymorphisms (His313 and Pro319) in the dopamine D2 receptor gene with schizophrenia using a case-control approach, with 101 cases and 145 controls. Our results demonstrated that genotype distribution for the His313 polymorphism was significantly different between schizophrenia patients and control subjects (p=0.0012), while the Pro319 polymorphism did not show any association with the disease. The results suggest that the synonymous SNP His313 in DRD2 may be associated with the illness. However, there is a need for further replication studies with larger sample sets.     

Polymorphisms in the vitamin D receptor and their associations with risk of schizophrenia and selected anthropometric measures.

The association between vitamin D levels and skeletal growth has long been recognized. However, exposure to low levels of vitamin D during early life is also known to alter brain development, and is a candidate risk factor for schizophrenia. This study examines the association between four polymorphisms in the vitamin D receptor (VDR) and 1) risk of schizophrenia, and 2) three anthropometric variables (height, head size, and head shape). Four single-nucleotide polymorphisms (SNPs; rs10735810/FokI, rs1544410/BsmI, rs7975232/ApaI, and rs731236/TaqI) in the VDR gene were genotyped in 179 individuals with schizophrenia and 189 healthy controls. No significant associations were detected between any of the four VDR SNPs and risk of schizophrenia. Patients were slightly but significantly shorter compared to controls. Of the four SNPs, only rs10735810/FokI was associated with any of the anthropometric measures: the M4 isoform of this SNP was significantly associated with larger head size (P = 0.002). In light of the evidence demonstrating a role for vitamin D during brain development, the association between polymorphisms in VDR and brain development warrants closer scrutiny.     

Genetic variation in the brain derived neurotrophic factor gene in Alzheimer's disease.

Genes known to contribute to the genetic predisposition to Alzheimer's disease (AD) are active in pathways of neurodegeneration but explain only a minority of the genetic contribution to AD. A protein of importance in cerebral neurodegeneration is the brain-derived neurotrophic factor (BDNF). Variations in two single-nucleotide polymorphisms (SNPs) within the BDNF gene have previously been associated with AD, and one of these SNPs has also been associated with memory loss and affective disorders. We performed a case control study of three BDNF SNPs in 250 neuropathologically confirmed cases of AD and 194 unrelated controls. We did not find a significant association between the three BDNF SNPs studied and AD when evaluated individually or with haplotype analysis. Nor did BDNF genotype appear to affect the APOE epsilon4 association with AD. The three SNPs studied were closely linked (D' = 0.99 across the region). We discuss possible reasons for our failure to confirm the previously reported associations.     

Visual attention deficits in Alzheimer's disease: an fMRI study

Cognitive and neuroscience studies indicate that attentional operations are impaired in Alzheimer's disease (AD). Our goal was to define the anatomical areas of activation associated with visual attention processing and to define deficits or changes that may occur in AD patients compared with control group. Thirteen AD patients and 13 age- and education-matched normal controls were tested in two visual search tasks (one was a conjunction task, where feature binding is required. The other was a subset task, where group stimuli is needed without feature binding) using fMRI techniques. After stereotactical normalization, voxel-by-voxel t statistics was used to compare activated brain areas between patients and control subjects. Our findings suggest that both search tasks are controlled by partially overlapping cerebral networks, including parietal, frontal and occipital-temporal cortical regions and primary visual cortex. The AD patient group showed less activation in both parietal lobes and the left frontal regions, while increased activation was found in the right frontal lobes and the right occipito-temporal cortical regions with the conjunction task. In the subset task, decreased activation in AD patients was seen in the left parietal lobe and bilateral frontal lobes, while increased activation was seen in both medial temporal lobes. In addition, for the comparison between tasks, The difference is very small for AD patients. Control group showed a higher amplitude in the right prefrontal region, temporal cortical regions and parietal lobe. These results indicate that attention deficits in AD patients may be attributed to both binding problem and grouping inefficiency.     

IGF1, growth pathway polymorphisms and schizophrenia: a pooling study.

It has been hypothesized that insulin-like growth factors (IGFs) and components of the growth-hormone (GH)-IGF axis may underlie reported associations of poor fetal and childhood growth with schizophrenia. We have investigated the association of schizophrenia with 16 SNPs spanning the IGF1 gene with an inter-marker distance of approximately 2-3 kb. We also examined associations with four common functional polymorphisms of genes involved in aspects of the GH-IGF system--the IGF1 receptor (IGF1R), insulin receptor substrate (IRS1), growth hormone (GH1), and IGF binding protein-3 (IGFBP3). The study was based on an analysis of pooled DNA samples from 648 UK and Irish cases of schizophrenia and 712 blood donor controls and of 297 Bulgarian parent offspring trios. In replicated pool analyses, none of the 16 SNPs in IGF1 nor the 4 key SNPs in the other growth pathway genes were associated with schizophrenia. SNP coverage of IGF1 was extensive, so our findings do not support a major role for IGF-I in the aetiology of schizophrenia.     

No associations exist between five functional polymorphisms in the catechol-O-methyltransferase gene and schizophrenia in a Japanese population

Catechol-O-methyltransferase (COMT) is one of the enzymes that degrade catecholamine neurotransmitters including dopamine. The COMT gene is located on 22q11.2, a common susceptibility locus for schizophrenia. Therefore, COMT is a strong functional and positional candidate gene for schizophrenia. A common functional polymorphism (rs4680, Val158Met) has been extensively tested for an association with schizophrenia, but with conflicting results. Recent studies indicate that if COMT is implicated in susceptibility to schizophrenia, this cannot be wholly accounted for by the Val158Met polymorphism. To assess this view, the authors conducted a case-control association study (399 patients with schizophrenia and 440 control subjects) for five functional polymorphisms (rs2075507, rs737865, rs6267, rs4680 and rs165599) in Japanese subjects. There were no significant associations found between the polymorphisms or haplotypes of COMT and schizophrenia. The present study shows that these five functional COMT polymorphisms do not play a major role in conferring susceptibility to schizophrenia in Japanese.