Search

Background The Human Natural Killer-1 carbohydrate (HNK-1) is involved in neurodevelopment and synaptic plasticity. Extracellular matrix structures called perineuronal nets, condensed around subsets of neurons and proximal dendrites during brain maturation, regulate synaptic transmission and plasticity. Methods Ten genes of importance for HNK-1 biosynthesis ( B3GAT1 , B3GAT2 , and CHST10 ) or for the formation of perineuronal nets ( TNR , BCAN , NCAN , HAPLN1 , HAPLN2 , HAPLN3 , and HAPLN4 ) were investigated for potential involvement in schizophrenia (SCZ) susceptibility, by genotyping 104 tagSNPs in the Scandinavian Collaboration on Psychiatric Etiology sample (849 cases; 1602 control subjects). Genome-wide association study imputation data from the European SGENE-plus sample (2663 cases; 13,498 control subjects) were used for comparison. The effect of SCZ risk alleles on brain structure was investigated in a Norwegian subset (98 cases; 177 control subjects) with structural magnetic resonance imaging data. Results Five single nucleotide polymorphisms (SNPs), located in two adjacent estimated linkage disequilibrium blocks in the first intron of β-1,3-glucuronyltransferase 2 ( B3GAT2 ), were nominally associated with SCZ (.004 ≤ P empirical ≤ .05). The rs2460691 was significantly associated in the comparison sample and in the meta-analysis after correction for all 121 SNP/haplotype tests ( P raw = 1 × 10 −4 ; P corrected = .018). Increased dosage of the rs2460691 SCZ risk allele was associated with decreased cortical area ( p = .002) but not thickness or hippocampal volume. A second SNP ( r 2 = .24 with rs10945275), which conferred the highest SCZ risk effect in the Norwegian subset, was also associated with cortical area. Conclusions The present results suggest that effects on biosynthesis of the neuronal epitope HNK-1, through common B3GAT2 variation, could increase the risk of SCZ, possibly by decreasing cortical area.

Background The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) in healthy humans and their ability to exacerbate psychotic symptoms in schizophrenic patients have promoted a view of schizophrenia as being related to altered glutamatergic neurotransmission. Methods This prompted us and others to develop animal models for psychosis based on a glutamatergic approach. Pharmacological induction of a state of impaired glutamatergic neurotransmission based on chronic, low-dose application of MK-801, a highly selective noncompetitive NMDA antagonist, revealed marked parallels between schizophrenia and our animal model. Results MK-801 altered the expression of NR1 splice variants and NR2 subunits of the NMDA receptor in a pattern partially resembling the alterations detected in schizophrenia. Ultrastructurally, the number of gamma-aminobutyric-acid (GABA)ergic parvalbumin-positive interneurons was relatively decreased, a finding which again parallels observations in post mortem brain from schizophrenic patients. As a functional consequence, local inhibition of pyramidal cells which is largely mediated by recurrent axon collaterals, originating from GABAergic interneurons, was altered. Not unexpectedly, these animals showed cognitive deficits resembling findings in schizophrenic humans. Conclusions These convergent lines of evidence suggest that our approach has a significant potential of serving as a model of the pathobiology of several aspects of psychosis and consequently could contribute to the development of new therapeutic strategies.

Background Neurobiological studies implicate serotonergic dysfunction in suicidal behavior. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin, plays a vital role in serotonin metabolism. Thus, variations in the TPH gene have been regarded as prime candidates in the susceptibility to suicidal behavior. The most widely studied genetic variations in the TPH gene, which are located in intron 7, yielded conflicting results in individual studies on suicide-related behavior. Methods We performed a meta-analysis on a total of 898 patients and 1179 control subjects, in addition to our local association study in consecutively recruited suicide attempters ( n = 147) and healthy control subjects of German descent ( n = 326). Results We observed a nonsignificant higher frequency of the TPH intron 7 A218 allele in our local group. The meta-analysis showed a weak yet highly significant increase in the frequency of the A218 allele (odds ratio [OR]: 1.33; 95% confidence interval [CI]: 1.17-1.50; p = .00002) and an over-representation of A-carriers (OR: 1.48; 95% CI: 1.22-1.79; p = .00005) in Caucasian suicide attempters/victims. Conclusions Our meta-analysis provides strong evidence for an association of suicide-related behavior with an A218 single-nucleotide polymorphism in the TPH gene in Caucasians. Because this variation do not seem to alter functional properties of the TPH gene or protein, functional variations remain to be identified and subsequently tested for association with suicide-related behavior.

Background Suicidal behavior is often correlated with other-directed aggression, which is partially mediated by catecholaminergic neurotransmission. Catechol-O-methyltransferase (COMT) is an enzyme involved in catecholamine inactivation. In this study, we examined the influence of a functional COMT (V158M) polymorphism on suicidal behavior and anger-related traits. Methods This polymorphism was examined in 149 German suicide attempters and 328 German control subjects. Both groups were administered self-report questionnaires for anger-related traits. Results There was no overall difference in allele/genotype frequency between patients and control subjects; however, the low-activity L-allele and genotype frequencies were higher among violent suicide attempters. For anger-related traits, a multivariate effect of the COMT genotype was observed after controlling for age and educational level. LL-carriers expressed their anger more outwardly, whereas HH-carriers expressed it more inwardly and reported more state anger, as assessed by the self-report questionnaire. Conclusions These findings support the hypothesis that the functional polymorphism in the COMT gene may modify the phenotype of suicide attempts and anger-related traits. This, however, being a novel finding, should warrant further investigation.

Background We have investigated which eye-movement tests alone and combined can best discriminate schizophrenia cases from control subjects and their predictive validity. Methods A training set of 88 schizophrenia cases and 88 controls had a range of eye movements recorded; the predictive validity of the tests was then examined on eye-movement data from 34 9-month retest cases and controls, and from 36 novel schizophrenia cases and 52 control subjects. Eye movements were recorded during smooth pursuit, fixation stability, and free-viewing tasks. Group differences on performance measures were examined by univariate and multivariate analyses. Model fitting was used to compare regression, boosted tree, and probabilistic neural network approaches. Results As a group, schizophrenia cases differed from control subjects on almost all eye-movement tests, including horizontal and Lissajous pursuit, visual scanpath, and fixation stability; fixation dispersal during free viewing was the best single discriminator. Effects were stable over time, and independent of sex, medication, or cigarette smoking. A boosted tree model achieved perfect separation of the 88 training cases from 88 control subjects; its predictive validity on retest assessments and novel cases and control subjects was 87.8%. However, when we examined the whole data set of 298 assessments, a cross-validated probabilistic neural network model was superior and could discriminate all cases from controls with near perfect accuracy at 98.3%. Conclusions Simple viewing patterns can detect eye-movement abnormalities that can discriminate schizophrenia cases from control subjects with exceptional accuracy.

Background Decreased sensitivity to and increased tolerance for the effects of alcohol is a phenotype, which was shown to be associated with an increased risk for alcoholism in humans and was observed in protein tyrosine kinase (PTK) fyn knockout mice. Methods We performed an association study of genetic variations of PTK fyn in 430 alcohol-dependent patients and 365 unrelated control subjects from two independent samples. Results In a combined analysis, we found an association of alcohol dependence with the single nucleotide polymorphism (SNP) T137346C in the 5′ untranslated region (UTR) of the gene. A relevant association could be excluded for the remaining two informative SNPs. Selection by phenotype showed that a high number of withdrawal symptoms, high amount of alcohol intake, and high maximum number of drinks compared with unrelated control subjects was associated with the SNP in the 5′-UTR region but not with the remaining SNPs. Conclusions Our results indicate a possible association of alcohol dependence with a genotype of the SNP T137346C of the PTK fyn, with C being the risk allele.