Genetic variants in COMT and neurocognitive impairment in families of patients with schizophrenia

This study examined the relations of genetic variants in catechol- O -methyltransferase ( COMT ) gene, including rs737865 in intron 1, rs4680 in exon 4 (Val158Met) and downstream rs165599, to schizophrenia and its related neurocognitive functions in families of patients with schizophrenia. Totally, 680 individuals from 166 simplex (166 affected members and 354 nonpsychotic first-degree relatives) and 46 multiplex families (85 affected members and 75 nonpsychotic first-degree relatives) were interviewed using Diagnostic Interview for Genetic Studies, administered Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT), and drawn for venous blood. Both categorical (dichotomizing families on affected members' neurocognitive performance) and quantitative approaches toward the WCST and CPT performance scores were employed using the family-based association test and the variance components framework, respectively. Both false discovery rate and permutations were used to adjust for multiple testing. The genotypes of rs4680 were associated with both the WCST and CPT performance scores in these families, but not with schizophrenia per se in either whole sample or subgroup analyses. Meanwhile, the other two single nucleotide polymorphisms were differentially associated with the two tasks. For WCST indexes, regardless of subgroup analyses or quantitative approach, only rs737865 exhibited moderate associations. For CPT indexes, rs737865 exhibited association for the subgroup with deficit on CPT reaction time, whereas rs165599 exhibited association for the subgroup with deficit on CPT d' as well as quantitative undegraded d'. Our results indicate that the genetic variants in COMT might be involved in modulation of neurocognitive functions and hence conferring increased risk to schizophrenia.     

MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.     

MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls

Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.     

The Associations between COMT and MAO-B Genetic Variants with Negative Symptoms in Patients with Schizophrenia

Negative symptoms of schizophrenia, including anhedonia, represent a heavy burden on patients and their relatives. These symptoms are associated with cortical hypodopamynergia and impaired striatal dopamine release in response to reward stimuli. Catechol-O-methyltransferase (COMT) and monoamine oxidase type B (MAO-B) degrade dopamine and affect its neurotransmission. The study determined the association between COMT rs4680 and rs4818, MAO-B rs1799836 and rs6651806 polymorphisms, the severity of negative symptoms, and physical and social anhedonia in schizophrenia. Sex-dependent associations were detected in a research sample of 302 patients with schizophrenia. In female patients with schizophrenia, the presence of the G allele or GG genotype of COMT rs4680 and rs4818, as well as GG haplotype rs4818-rs4680, which were all related to higher COMT activity, was associated with an increase in several dimensions of negative symptoms and anhedonia. In male patients with schizophrenia, carriers of the MAO-B rs1799836 A allele, presumably associated with higher MAO-B activity, had a higher severity of alogia, while carriers of the A allele of the MAO-B rs6651806 had a higher severity of negative symptoms. These findings suggest that higher dopamine degradation, associated with COMT and MAO-B genetic variants, is associated with a sex-specific increase in the severity of negative symptoms in schizophrenia patients.     

A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain

The gene encoding catechol-O-methyltransferase (COMT) is a strong candidate for schizophrenia susceptibility, owing to the role of COMT in dopamine metabolism, and the location of the gene within the deleted region in velocardiofacial syndrome, a disorder associated with high rates of schizophrenia. Recently, a highly significant association was reported between schizophrenia and a COMT haplotype in a large case-control sample (Shifman et al. 2002). In addition to a functional valine-->methionine (Val/Met) polymorphism, this haplotype included two noncoding single-nucleotide polymorphisms (SNPs) at either end of the COMT gene. Given the role of COMT in dopamine catabolism and that deletion of 22q11 (containing COMT) is associated with schizophrenia, we postulated that the susceptibility COMT haplotype is associated with low COMT expression. To test this hypothesis, we have applied quantitative measures of allele-specific expression using mRNA from human brain. We demonstrate that COMT is subject to allelic differences in expression in human brain and that the COMT haplotype implicated in schizophrenia (Shifman et al. 2002) is associated with lower expression of COMT mRNA. We also show that the 3' flanking region SNP that gave greatest evidence for association with schizophrenia in that study is transcribed in human brain and exhibits significant differences in allelic expression, with lower relative expression of the associated allele. Our results indicate that COMT variants other than the Val/Met change are of functional importance in human brain and that the haplotype implicated in schizophrenia susceptibility is likely to exert its effect, directly or indirectly, by down-regulating COMT expression.     

Plasma total homocysteine is associated with DNA methylation in patients with schizophrenia

Schizophrenia (SCZ) is a devastating psychiatric disorder with a median lifetime prevalence rate of 0.7–0.8%. Elevated plasma total homocysteine has been suggested as a risk factor for SCZ, and various biological effects of hyperhomocysteinemia have been proposed to be relevant to the pathophysiology of SCZ. As increased attention is paid to aberrant DNA methylation in SCZ, homocysteine is attracting additional interest as a potential key substance. Homocysteine is formed in the methionine cycle, which is involved in one-carbon methyl group-transfer metabolism, and it acts as a methyl donor when it is converted to S-adenosyl-methionine. To date, no studies have examined the relationship between homocysteine and genome-wide DNA methylation in SCZ. We examined the relationship between plasma total homocysteine and DNA methylation patterns in the peripheral leukocytes of patients with SCZ (n = 42) using a quantitative high-resolution DNA methylation array (485,764 CpG sites). Significant homocysteine-related changes in DNA methylation were observed at 1,338 CpG sites that were located across whole gene regions, including promoters, gene bodies and 3′-untranslated regions. Of the 1,338 sites, 758 sites (56.6%) were located in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 15.8%; CGI shore: 28.2%; CGI shelf: 12.6%), and positive correlations between plasma total homocysteine and DNA methylation were observed predominantly at CpG sites in the CGIs. Our results suggest that homocysteine might play a role in the pathogenesis of SCZ via a molecular mechanism that involves alterations to DNA methylation.     

COMT rs4680 Met is not always the ‘smart allele’: Val allele is associated with better working memory and larger hippocampal volume in healthy Chinese

Catechol‐O‐methyltransferase (COMT) Val158Met (rs4680) polymorphism plays a crucial role in regulating brain dopamine level. Converging evidence from Caucasian samples showed that, compared with rs4680 Val allele, the Met allele was linked to lower COMT activity, which in turn was linked to better cognitive performance such as working memory (WM) and to a larger hippocampus (a brain region important for WM). However, some behavioral studies have shown that the function of rs4680 appears to vary across different ethnic groups, with Chinese subjects showing an opposite pattern as that for Caucasians (i.e. the Val allele is linked to better cognitive functions related to WM in Chinese). Using a sample of healthy Han Chinese college students (ages from 19 to 21 years), this study investigated the association of COMT Val158Met genotype with behavioral data on a two‐back WM task (n = 443, 189M/254F) and T1 MRI data (n = 320, 134M/186F). Results showed that, compared to the Met allele, the Val allele was associated with larger hippocampal volume (the right hippocampus: β = ?0.118, t = ?2.367, P = 0.019, and the left hippocampus: β = ?0.099, t = ?1.949, P = 0.052) and better WM performance (β = ?0.110, t = ?2.315, P = 0.021). These results add to the growing literature on differentiated effects of COMT rs4680 polymorphism on WM across populations and offer a brain structural mechanism for such population‐specific genetic effects.     

Identifying the brain regions associated with acute spasticity in patients diagnosed with an ischemic stroke

Spasticity is a common impairment found in patients that have been diagnosed with a stroke. Little is known about the pathophysiology of spasticity at the level of the brain. This retrospective study was performed to identify an association between the area of the brain affected by an ischemic stroke and the presence of acute spasticity. Physical and occupational therapy assessments from all patients (n?=?441) that had suffered a stroke and were admitted into a local hospital over a 4-year period were screened for inclusion in this study. Subjects that fit the inclusion criteria were grouped according to the presence (n?=?42) or absence (n?=?129) of acute spasticity by the Modified Ashworth Scale score given during the hospital admission assessment. Magnetic resonance images from 20 subjects in the spasticity group and 52 from the control group were then compared using lesion density plots and voxel-based lesion–symptom mapping. An association of acute spasticity with the gray matter regions of the insula, basal ganglia, and thalamus was found in this study. White matter tracts including the pontine crossing tract, corticospinal tract, internal capsule, corona radiata, external capsule, and the superior fronto-occipital fasciculus were also found to be significantly associated with acute spasticity. This is the first study to describe an association between a region of the brain affected by an infarct and the presence of acute spasticity. Understanding the regions associated with acute spasticity will aid in understanding the pathophysiology of this musculoskeletal impairment at the level of the brain.     

Sexual selection impacts brain anatomy in frogs and toads

Natural selection is a major force in the evolution of vertebrate brain size, but the role of sexual selection in brain size evolution remains enigmatic. At least two opposing schools of thought predict a relationship between sexual selection and brain size. Sexual selection should facilitate the evolution of larger brains because better cognitive abilities may aid the competition for mates. However, it may also restrict brain size evolution due to energetic trade‐offs between brain tissue and sexually selected traits. Here, we examined the patterns of selection on brain size and brain anatomy in male anurans (frogs and toads), a group where the strength of sexual selection differs markedly among species, using a phylogenetically controlled generalized least‐squared (PGLS) regression analyses. The analysis revealed that in 43 Chinese anuran species, neither mating system, nor type of courtship, or testes mass was significantly associated with relative brain size. While none of those factors related to the relative size of olfactory nerves, optic tecta, telencephalon, and cerebellum, the olfactory bulbs were relatively larger in monogamous species and those using calls during courtship. Our findings support the mosaic model of brain evolution and suggest that while the investigated aspects of sexual selection do not seem to play a prominent role in the evolution of brain size of anurans, they do impact their brain anatomy.     

COMT Val158Met genotype is associated with reward learning: a replication study and meta‐analysis

Identifying mechanisms through which individual differences in reward learning emerge offers an opportunity to understand both a fundamental form of adaptive responding as well as etiological pathways through which aberrant reward learning may contribute to maladaptive behaviors and psychopathology. One candidate mechanism through which individual differences in reward learning may emerge is variability in dopaminergic reinforcement signaling. A common functional polymorphism within the catechol‐O‐methyl transferase gene (COMT; rs4680, Val¹⁵⁸Met) has been linked to reward learning, where homozygosity for the Met allele (linked to heightened prefrontal dopamine function and decreased dopamine synthesis in the midbrain) has been associated with relatively increased reward learning. Here, we used a probabilistic reward learning task to asses response bias, a behavioral form of reward learning, across three separate samples that were combined for analyses (age: 21.80 ± 3.95; n = 392; 268 female; European‐American: n = 208). We replicate prior reports that COMT rs4680 Met allele homozygosity is associated with increased reward learning in European‐American participants (β = 0.20, t = 2.75, P < 0.01; ΔR² = 0.04). Moreover, a meta‐analysis of 4 studies, including the current one, confirmed the association between COMT rs4680 genotype and reward learning (95% CI ?0.11 to ?0.03; z = 3.2; P < 0.01). These results suggest that variability in dopamine signaling associated with COMT rs4680 influences individual differences in reward which may potentially contribute to psychopathology characterized by reward dysfunction.     

Increased brain size in mammals is associated with size variations in gene families with cell signalling,chemotaxis and immune-related functions

Genomic determinants underlying increased encephalization across mammalian lineages are unknown. Whole genome comparisons have revealed large and frequent changes in the size of gene families, and it has been proposed that these variations could play a major role in shaping morphological and physiological differences among species. Using a genome-wide comparative approach, we examined changes in gene family size (GFS) and degree of encephalization in 39 fully sequenced mammalian species and found a significant over-representation of GFS variations in line with increased encephalization in mammals. We found that this relationship is not accounted for by known correlates of brain size such as maximum lifespan or body size and is not explained by phylogenetic relatedness. Genes involved in chemotaxis, immune regulation and cell signalling-related functions are significantly over-represented among those gene families most highly correlated with encephalization. Genes within these families are prominently expressed in the human brain, particularly the cortex, and organized in co-expression modules that display distinct temporal patterns of expression in the developing cortex. Our results suggest that changes in GFS associated with encephalization represent an evolutionary response to the specific functional requirements underlying increased brain size in mammals.     

Theory of mind and the social brain: implications for understanding the genetic basis of schizophrenia

Genome‐wide association studies in schizophrenia have recently made significant progress in our understanding of the complex genetic architecture of this disorder. Many genetic loci have been identified and now require functional investigation. One approach involves studying their correlation with neuroimaging and neurocognitive endophenotypes. Theory of Mind (ToM) deficits are well established in schizophrenia and they appear to fulfill criteria for being considered an endophenotype. We aim to review the behavioral and neuroimaging‐based studies of ToM in schizophrenia, assess its suitability as an endophenotype, discuss current findings, and propose future research directions. Suitable research articles were sourced from a comprehensive literature search and from references identified through other studies. ToM deficits are repeatable, stable, and heritable: First‐episode patients, those in remission and unaffected relatives all show deficits. Activation and structural differences in brain regions believed important for ToM are also consistently reported in schizophrenia patients at all stages of illness, although no research to date has examined unaffected relatives. Studies using ToM as an endophenotype are providing interesting genetic associations with both single nucleotide polymorphisms (SNPs) and specific copy number variations (CNVs) such as the 22q11.2 deletion syndrome. We conclude that ToM is an important cognitive endophenotype for consideration in future studies addressing the complex genetic architecture of schizophrenia, and may help identify more homogeneous clinical sub‐types for further study     

No association of Disrupted-in-Schizophrenia-1 variation with prefrontal function in patients with schizophrenia and bipolar disorder

The Disrupted-in-Schizophrenia-1 (DISC1) gene has been implicated in both schizophrenia and bipolar disorder by linkage and genetic association studies. Altered prefrontal cortical function is a pathophysiological feature of both disorders, and we have recently shown that variation in DISC1 modulates prefrontal activation in healthy volunteers. Our goal was to examine the influence of the DISC1 polymorphism Cys704Ser on prefrontal function in schizophrenia and bipolar disorder. From 2004 to 2008, patients with schizophrenia (N = 44), patients with bipolar disorder (N = 35) and healthy volunteers (N = 53) were studied using functional magnetic resonance imaging while performing a verbal fluency task. The effect of Cys704Ser on cortical activation was compared between groups as Cys704 carriers vs. Ser704 homozygotes. In contrast to the significant effect on prefrontal activation we had previously found in healthy subjects, no significant effect of Cys704Ser was detected in this or any other region in either the schizophrenia or bipolar groups. When controls were compared with patients with schizophrenia, there was a diagnosis by genotype interaction in the left middle/superior frontal gyrus [family-wise error (FWE) P = 0.002]. In this region, Ser704/ser704 controls activated more than Cys704 carriers, and there was a trend in the opposite direction in schizophrenia patients. In contrast to its effect in healthy subjects, variation in DISC1 Cys704Ser704 genotype was not associated with altered prefrontal activation in patients with schizophrenia or bipolar disorder. The absence of an effect in patients may reflect interactions of the effects of DISC1 genotype with the effects of other genes associated with these disorders, and/or with the effects of the disorders on brain function.     

Longevity is associated with relative brain size in birds

Brain size of vertebrates has long been recognized to evolve in close association with basic life‐history traits, including lifespan. According to the cognitive buffer hypothesis, large brains facilitate the construction of behavioral responses against novel socioecological challenges through general cognitive processes, which should reduce mortality and increase lifespan. While the occurrence of brain size–lifespan correlation has been well documented in mammals, much less evidence exists for a robust link between brain size and longevity in birds. The aim of this study was to use phylogenetically controlled comparative approach to test for the relationship between brain size and longevity among 384 avian species from 23 orders. We used maximum lifespan and maximum reproductive lifespan as the measures of longevity and accounted for a set of possible confounding effects, such as allometry, sampling effort, geographic patterns, and life‐history components (clutch size, incubation length, and mode of development). We found that both measures of longevity positively correlated with relative (residual) brain size. We also showed that major diversification of brain size preceded diversification of longevity in avian evolution. In contrast to previous findings, the effect of brain size on longevity was consistent across lineages with different development patterns, although the relatively low strength of this correlation could likely be attributed to the ubiquity of allomaternal care associated with the altricial mode of development. Our study indicates that the positive relationship between brain size and longevity in birds may be more general than previously thought.     

Heat shock protein 70 gene polymorphisms are associated with paranoid schizophrenia in the Polish population

HSP70 genes have been considered as promising schizophrenia candidate genes based on their protective role in the central nervous system under stress conditions. In this study, we analyzed the potential implication of HSPA1A +190G/C, HSPA1B +1267A/G, and HSPA1L +2437T/C polymorphisms in the susceptibility to paranoid schizophrenia in a homogenous Caucasian Polish population. In addition, we investigated the association of the polymorphisms with the clinical variables of the disease. Two hundred and three patients with paranoid schizophrenia and 243 healthy controls were enrolled in the study. Polymorphisms of HSPA1A, -1B, and -1L genes were genotyped using the PCR-RFLP technique. Analyses were conducted in entire groups and in subgroups that were stratified according to gender. There were significant differences in the genotype and allele frequencies of HSPA1A polymorphism between the patients and controls. The +190CC genotype and +190C allele were over-represented in the patients and significantly increased the risk for developing schizophrenia (OR = 3.45 and OR = 1.61, respectively). Interestingly, such a risk was higher for females with the +190CC genotype than for males with the +190CC genotype (OR = 5.78 vs. OR = 2.76). We also identified the CGT haplotype as a risk haplotype for schizophrenia and demonstrated the effects of HSPA1A and HSPA1B genotypes on the psychopathology and age of onset. Our study provided the first evidence that the HSPA1A polymorphism may potentially increase the risk of developing paranoid schizophrenia. Further independent analyses in different populations to evaluate the role of gender are needed to replicate these results.     

Genetic variation in DNMT3B and increased global DNA methylation is associated with suicide attempts in psychiatric patients

Recently, a significant epigenetic component in the pathology of suicide has been realized. Here we investigate candidate functional SNPs in epigenetic‐regulatory genes, DNMT1 and DNMT3B, for association with suicide attempt (SA) among patients with co‐existing psychiatric illness. In addition, global DNA methylation levels [5‐methyl cytosine (5‐mC%)] between SA and psychiatric controls were quantified using the Methylflash Methylated DNA Quantification Kit. DNA was obtained from blood of 79 suicide attempters and 80 non‐attempters, assessed for DSM‐IV Axis I disorders. Functional SNPs were selected for each gene (DNMT1; n = 7, DNMT3B; n = 10), and genotyped. A SNP (rs2424932) residing in the 3′ UTR of the DNMT3B gene was associated with SA compared with a non‐attempter control group (P = 0.001; Chi‐squared test, Bonferroni adjusted P value = 0.02). Moreover, haplotype analysis identified a DNMT3B haplotype which differed between cases and controls, however this association did not hold after Bonferroni correction (P = 0.01, Bonferroni adjusted P value = 0.56). Global methylation analysis showed that psychiatric patients with a history of SA had significantly higher levels of global DNA methylation compared with controls (P = 0.018, Student's t‐test). In conclusion, this is the first report investigating polymorphisms in DNMT genes and global DNA methylation quantification in SA risk. Preliminary findings suggest that allelic variability in DNMT3B may be relevant to the underlying diathesis for suicidal acts and our findings support the hypothesis that aberrant DNA methylation profiles may contribute to the biology of suicidal acts. Thus, analysis of global DNA hypermethylation in blood may represent a biomarker for increased SA risk in psychiatric patients.     

TTLL11 gene is associated with sustained attention performance and brain networks: A genome-wide association study of a healthy Chinese sample

Genetic studies on attention have mainly focused on children with attention-deficit/hyperactivity disorder (ADHD), so little systematic research has been conducted on genetic correlates of attention performance and their potential brain mechanisms among healthy individuals. The current study included a genome-wide association study (GWAS, N = 1145 healthy young adults) aimed to identify genes associated with sustained attention and an imaging genetics study (an independent sample of 483 healthy young adults) to examine any identified genes' influences on brain function. The GWAS found that TTLL11 showed genome-wide significant associations with sustained attention, with rs13298112 as the most significant SNP and the GG homozygotes showing more impulsive but also more focused responses than the A allele carriers. A retrospective examination of previously published ADHD GWAS results confirmed an un-reported, small but statistically significant effect of TTLL11 on ADHD. The imaging genetics study replicated this association and showed that the TTLL11 gene was associated with resting state activity and connectivity of the somatomoter network, and can be predicted by dorsal attention network connectivity. Specifically, the GG homozygotes showed lower brain activity, weaker brain network connectivity, and non-significant brain-attention association compared to the A allele carriers. Expression database showed that expression of this gene is enriched in the brain and that the G allele is associated with lower expression level than the A allele. These results suggest that TTLL11 may play a major role in healthy individuals' attention performance and may also contribute to the etiology of ADHD.