The interrelationship of body mass index with gray matter volume and resting-state functional connectivity of the hypothalamus.

BACKGROUND: The hypothalamus plays an important role in regulating body weight through its interactions with multiple brain circuits involved in distinct aspects of feeding behavior. Yet, how hypothalamic gray matter volume (GMV) and connectivity may be related to individual differences in body weight remains unclear. We tested the hypothesis that the hypothalamus shows enhanced resting-state functional connectivity (rsFC) with regions of the reward, motivation, and motor circuits in positive correlation with body mass index (BMI) and the opposite with those associated with inhibitory control. We further examined the interdependent relationships between hypothalamic GMV, connectivity, and body weight. METHODS: Using seed-based rsFC and voxel-based morphometry analyses, we examined the relationship between the rsFC and GMV of the hypothalamus and BMI in 105 healthy humans. Additionally, we employed mediation analyses to characterize the inter-relationships between hypothalamic connectivity, GMV, and BMI. RESULTS: A whole-brain multiple regression showed that BMI was positively correlated with hypothalamic rsFC with the insula, thalamus, globus pallidus, and cerebellum, and negatively correlated with hypothalamic rsFC with the superior parietal lobule. Thus, higher BMI was associated with enhanced hypothalamic connectivity with regions involved in motivated feeding and reduced connectivity with those in support of cognitive control of food intake. A second whole-brain multiple regression revealed a positive correlation between hypothalamic GMV and the hypothalamus-posterior insula connectivity. Finally, the relationship between hypothalamic GMV and BMI was significantly and bidirectionally mediated by the hypothalamus-posterior insula connectivity. CONCLUSIONS: The current findings suggest that the hypothalamus differentially interacts with the motivation, motor, and control circuits to regulate BMI. We further found evidence for the interdependence of hypothalamic structure, function, and body weight, which provides potential insights into the brain mechanisms of obesity.

The effectiveness of long-acting injectable antipsychotics versus oral antipsychotics in the maintenance treatment of outpatients with chronic schizophrenia.

OBJECTIVE: To compare the psychiatric service utilization between patients who only received long-acting injectable antipsychotics (LAIAs) and those who only received oral antipsychotics (OAPs) in the maintenance treatment of chronic schizophrenia. METHODS: We constructed a cohort of chronic schizophrenia patients who underwent maintenance treatment from the Taiwan National Health Insurance Research Database in 2011 and followed these patients for 12 months. We included patients who had been diagnosed with schizophrenia for at least 3 years, were not hospitalized in 2011, and had received 1 year of maintenance treatment. Inverse probability of treatment weighting logistic, linear, and negative binomial regression models were used to estimate associated psychiatric services utilization and adjust for covariate imbalances between the LAIAs and OAPs groups. RESULTS: Among 40,194 patients, 948 (2.36%) received only LAIAs and 39,246 (97.64%) received only OAPs. Compared with those who received only OAPs, the sole LAIAs users were associated with a lower percentage of psychiatric hospitalization (8.4% and 5.8%, respectively; odds ratio: 0.63, p < .01), shorter lengths of hospitalization days (82.8 and 65.9, respectively; coefficient [b]: -16.87, p = .03), and fewer emergency room visits (2.3 and 1.8, respectively; b: -0.24, p < .01) per patient. CONCLUSIONS: Chronic schizophrenia patients who received only LAIs had a lower risk of disease relapse and a reduction in psychiatric service utilization than those receiving only OAPs.

Comparative gene expression profiling analysis of lymphoblastoid cells reveals neuron-specific enolase gene (ENO2) as a susceptibility gene of heroin dependence.

Heroin dependence is a complex mental disorder resulting from interactions between genetic and environmental factors. Identifying the susceptibility genes of heroin dependence is the basis for understanding the pathogenesis of heroin dependence. Using a total gene expression microarray, we detected 924 differentially expressed gene transcripts in lymphoblastoid cell lines (LCLs) between 19 male heroin-dependent individuals and 20 male control subjects, including 279 upregulated and 645 downregulated gene transcripts in heroin-dependent individuals. We verified the reduced expression of the neuron-specific enolase gene (ENO2) in heroin-dependent individuals using real-time quantitative polymerase chain reaction and Western blot analysis. We further compared the allele and genotype frequencies of three single nucleotide polymorphisms (SNPs, rs11064464, rs3213433 and rs10849541) of the ENO2 gene between 532 male heroin-dependent individuals and 369 male controls. No significant differences in the allele or genotype frequencies of these three SNPs were detected between these two groups. Nevertheless, we identified a haplotype (T-C-G) derived from these three SNPs significantly underrepresented in heroin-dependent individuals compared with the control group (72.7% versus 75.9%, P<0.032), while two other rare haplotypes (C-A-G and T-C-A) significantly overrepresented in heroin-dependent individuals compared with the control group (P<0.001). Further study, however, did not detect significant differences of the plasma concentration of neuron-specific enolase between these two groups. Our data suggest that the ENO2 gene might be associated with heroin dependence, and reduced ENO2 gene expression may confer increased risk to heroin dependence.

Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia.

Schizophrenia is a severe chronic mental disorder with a high genetic component in its etiology. Several lines of study have suggested that synaptic dysfunction may underlie the pathogenesis of schizophrenia. Neuroligin proteins function as cell-adhesion molecules at post-synaptic membrane and play critical roles in synaptogenesis and synaptic maturation. In this study, we systemically sequenced all the exons and promoter region of neuroligin-2 (NLGN2) gene in a sample of 584 schizophrenia patients and 549 control subjects from Taiwan. In total, we identified 19 genetic variants, including six rare missense mutations such as R215H (one patient), V510M (two patients), R621H (one patient), A637T (two patients), P800L (one patient and one control) and A819S (one patient and one control). In silico analysis predicted that two patient-specific missense mutations, R215H and R621H, had damaging effect, whereas the other missense mutations were benign. Importantly, functional analysis with immunocytochemistry and electrophysiological recordings identified the R215H mutant as a loss-of-function mutant in inducing GABAergic synaptogenesis. Mechanistically, the synaptogenic deficiency of R215H mutant was due to its retention inside the endoplasmic reticulum and inability to be transported to cell membrane. Our study suggests that defects in GABAergic synapse formation in the brain may be an important contributing factor for the onset of schizophrenia. In the family study of this mutation, we found his elder brother also carried this mutation but did not have psychiatric symptoms, indicating that this mutation has incomplete penetrance, and thus the clinical relevance of this mutation should be interpreted with caution.

Dose-response analysis of aripiprazole in patients with schizophrenia in Taiwan.

Background: Aripiprazole is a third-generation antipsychotic agent with acceptable efficacy and a good safety profile. Previous studies have indicated the therapeutic serum concentration of aripiprazole to be 100 to 350 ng/ml; however, most of these studies examined a Western population. Patients with schizophrenia from Tungs' Taichung MetroHarbor Hospital in central Taiwan were recruited to analyze the dose-response relationship of aripiprazole in the Chinese population. Objective: We aimed to investigate whether a serum concentration of aripiprazole higher than the current suggested range leads to higher response rates. Design: A prospective cohort study was designed to investigate the response rates in different studied cohorts grouped by serum concentration of aripiprazole. Data Sources and Methods: Data of 64 patients who presented to a single medical center in central Taiwan and who received therapeutic drug monitoring (TDM) were obtained. Serum concentrations of aripiprazole were correlated with the clinical response of patients by using the Clinical Global Impressions (CGI) scores. Results: The mean concentration of aripiprazole was 432.1 ± 275.1 ng/ml in the study cohort. Among the much-improved patients, the mean serum concentration of aripiprazole was 494 ± 273 ng/ml (25th-75th percentiles 264-666 ng/ml), which was higher than the current recommended therapeutic target of 100-350 ng/ml for aripiprazole. The response rate in the severe group (baseline CGI score of 6 or 7) was significantly higher than in the moderate group (baseline CGI score of 4 or 5; 86.7% versus 55.9%, p = 0.007). Conclusion: A significantly higher response rate was observed in the study cohort with serum aripiprazole concentrations over 300 ng/ml. Therefore, dosing higher than the current recommended range may potentially improve the treatment efficacy in the Chinese population. Because the serum concentration varies among patients due to multiple intrinsic and extrinsic factors, TDM, especially in outpatients, is recommended if the clinical response is limited.

Analysis of genetic variations in the dopamine D1 receptor (DRD1) gene and antipsychotics-induced tardive dyskinesia in schizophrenia.

BACKGROUND: Dyskinesia is a kind of abnormal involuntary movement disorder that increases with age. The pathogenesis of dyskinesia may result from divergent changes in dopamine D1 receptors (DRD1) and dopamine D2 receptors (DRD2) in the brain while aging. Tardive dyskinesia (TD), a kind of dyskinesia, may develop after long-term antipsychotic treatment. Because the prevalence of TD also steadily increased with age, TD has been suggested to be the consequence of an imbalance between DRD1 and DRD2. We supposed that patients who develop TD may have genetic variants of DRD1 that cause the excitatory effects of DRD1 overwhelming the attenuated inhibitory effects of DRD2 after antipsychotic treatment. METHODS: In the present study, schizophrenic inpatients receiving long-term antipsychotic treatment were first assessed using the Abnormal Involuntary Movement Scale (AIMS), and only patients who were either free of any abnormal involuntary movements (non-TD group, AIMS =0) or who showed persistent TD (TD group) were enrolled. Finally, 382 patients were recruited (TD=220, non-TD=162) and three single nucleus polymorphisms (SNPs; rs5326, rs4532 and rs265975) of DRD1 were genotyped for each subject. RESULTS: Genotype frequency (%; AA/AG/GG) of rs4532 (TD: non-TD) was 61.4/35.8/2.8: 74.2/24.5/1.3. After genetic analyses, genotype GG showed significant association with TD (if OR=2.0, power (%)=98.5; if OR=1.5, power (%)=63.7; P=0.033). Haplotype frequency (%) CGC of rs5326-rs4532-rs265975 (TD: non-TD) was 19.0:13.7; and after haplotype-based analyses, haplotype CGC also showed significant association with TD (OR=1.4, permutation P=0.027). CONCLUSION: Our results indicate that the genotypic variants of DRD1 might play a role in the susceptibility of TD. Further replication in other countries or other populations is highly expected.

Identification of Rare Mutations of Two Presynaptic Cytomatrix Genes BSN and PCLO in Schizophrenia and Bipolar Disorder.

Schizophrenia and bipolar disorder are severe mental disorders with a major component of genetic factors in their etiology. Rare mutations play a significant role in these two disorders, and they are highly heterogeneous and personalized. Identification of personalized mutations is essential for the establishment of molecular diagnosis, providing insight into pathogenesis and guiding the personalized treatment for each affected patient. We conducted whole-genome sequencing analysis of families with schizophrenia and bipolar disorder to search for their genetic underpinnings. This report identified a rare missense mutation Arg1087Gln of BSN (bassoon presynaptic cytomatrix protein) co-segregating with schizophrenia in a family with multiple affected members. Furthermore, we identified the rare missense mutation Ser1535Leu of PCLO (piccolo presynaptic cytomatrix protein) in two sisters with bipolar disorder and another rare missense mutation, His5142Arg in PCLO, in a patient with schizophrenia. These three missense mutations were very rare and were predicted to be pathogenic. The BSN and PCLO genes encode two structurally related proteins of the presynaptic cytomatrix at the active zone that regulates neurotransmission at the presynaptic neuronal terminal. Our findings suggest the involvement of the presynaptic matrix in the pathogenesis of schizophrenia and bipolar disorder, and BSN and PCLO are the risk genes for schizophrenia and bipolar disorder.

Analysis of genetic variations in the RGS9 gene and antipsychotic-induced tardive dyskinesia in schizophrenia.

Some patients treated chronically with antipsychotics develop tardive dyskinesia (TD), an abnormal involuntary movement disorder. Typical antipsychotics block D(2) dopamine receptors (D(2)DR) and produce D(2)DR supersensitivity. On contrary, regulators of G-protein signaling (RGS) can enhance the signal termination of G-protein-coupled D(2)DR. Besides, after prolonged inhibition of dopaminergic transmission, dopaminergic agonists induced severe dyskinesia only in RGS9 knock-out mice but not in normal mice. Therefore, variety in the human RGS9 gene may be related to susceptibility to TD. In this study, schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale twice over a 3-month interval. Only patients in whom abnormal involuntary movements were absent (non-TD group) and those who showed persistent TD (TD group) were enrolled. There were 407 patients in the study sample (TD = 252; non-TD = 155) and seven single nucleus polymorphisms (SNPs) in the RGS9 gene were genotyped for each subject. Genotype and allelic distributions of SNPs did not differ between the TD and non-TD groups in this study, with the exception that a weak trend of allelic association was seen with rs4790953 (P = 0.0399). In the haplotype analysis, a significant association of the AGG haplotype (rs8077696-rs8070231-rs2292593) of the RGS9 gene was found (permutation P = 0.007), and this is worthy of replication and further study.

Associations among antipsychotics, metabolism-related diseases, and cataracts in patients with schizophrenia: A retrospective cohort study.

BACKGROUND: Long-term cataract risks associated with first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), and their associations with metabolism-related diseases are not yet elucidated. METHODS: Using Taiwan National Health Insurance data, we conducted a propensity score matched population-based cohort study consisting of 10,014 patients with newly diagnosed schizophrenia from 2005 to 2009 and followed them until the end of 2013. A Cox hazard model with metabolism-related diseases as time-dependent covariates was adapted to estimate the hazard ratio (HR) of cataracts between SGAs and FGAs groups. RESULTS: During the 8-year follow-up, patients receiving SGAs were associated with a higher risk of cataract than those receiving FGAs with an adjusted HR of 1.59 (95% confidence interval [CI] = 1.06-2.36). Patients receiving high-metabolic-risk SGAs (clozapine and olanzapine) showed the highest risk of cataracts among SGAs when compared with those receiving FGAs (aHR = 2.57, 95% CI: 1.35-4.88). SGAs demonstrated a stronger contribution in the risk of cataract in patients without diabetes mellitus (DM) and hyperlipidemia than in those developed these diseases. Patients who developed DM or hyperlipidemia after receiving antipsychotics had an approximately 2.5-fold increased cataract risk over those who did not develop these diseases. CONCLUSIONS: Regardless of the condition of metabolic-related diseases, SGAs were independently associated with an increased risk of cataract. DM and hyperlipidemia developed after antipsychotics contributed to the risk of cataract risk.

Construction and Analysis of Protein-Protein Interaction Network of Heroin Use Disorder.

Heroin use disorder (HUD) is a complex disease resulting from interactions among genetic and other factors (e.g., environmental factors). The mechanism of HUD development remains unknown. Newly developed network medicine tools provide a platform for exploring complex diseases at the system level. This study proposes that protein-protein interactions (PPIs), particularly those among proteins encoded by casual or susceptibility genes, are extremely crucial for HUD development. The giant component of our constructed PPI network comprised 111 nodes with 553 edges, including 16 proteins with large degree (k) or high betweenness centrality (BC), which were further identified as the backbone of the network. JUN with the largest degree was suggested to be central to the PPI network associated with HUD. Moreover, PCK1 with the highest BC and MAPK14 with the secondary largest degree and 9th highest BC might be involved in the development HUD and other substance diseases.

Association study of HLA-A gene and schizophrenia in Han Chinese from Taiwan.

Dysregulation of the immune response has been proposed as a precipitating factor of schizophrenia, and human leukocyte antigens (HLA) play a critical role in regulating the cascade of immunological reaction. Hence, many studies have investigated the relationship between the HLA system and schizophrenia. HLA is a complex gene family that contains several highly polymorphic genes, while the HLA-A gene is the most often studied gene to be associated with schizophrenia in the literature. A recent study reported that the interaction of the HLA-A10 allele and Chlamydial infection was highly associated with schizophrenia in a German population, which prompted us to investigate whether the HLA-A gene was also associated with schizophrenia in our population. Using a sequencing-based HLA typing method, we determined the HLA-A genotypes in 377 Han Chinese patients with schizophrenia (214 males, 163 females) and 321 non-psychotic Han Chinese control subjects (164 males, 157 females) from Taiwan. In total, 26 DNA-defined HLA-A alleles were identified in this sample. However, no significant differences of these allelic frequencies were found between the patients and the control subjects, suggesting that the HLA-A gene was unlikely a major risk factor of schizophrenia in this sample. As different populations have different HLA polymorphisms, an examination of the relationship of other HLA genes and schizophrenia in our population, with a larger sample size, is warranted in the future.

Association of missense variants of the PRKC, apoptosis, WT1, regulator (PAWR) gene with schizophrenia.

Abnormal dopamine signal transduction is implicated in the pathophysiology of schizophrenia. A recent study showed that prostate apoptosis response 4 protein (Par-4) interacts with dopamine D2 receptor and plays an important role in dopamine signaling. Par-4 knockout mice showed depression-like behavior, suggesting that Par-4 gene may be associated with mental disorders in human. The study was aimed to determine whether the PRKC, apoptosis, WT1, regulator gene (PAWR) that encodes the human homolog of Par-4 protein is a susceptibility gene for schizophrenia. We systematically screened for mutations at the 5' untranslated region (5'UTR) and all the exonic regions of the PAWR gene in a sample of Han Chinese schizophrenic patients from Taiwan. We identified two missense single nucleotide polymorphisms (SNPs) that are in strong linkage in our sample (D'=0.98), i.e. P78R at exon 2 and I199M at exon 3, respectively. SNP- and haplotype-based analysis showed that these two variants are associated with schizophrenia; there is an overrepresentation of RR homozygotes of P78R (OR=2.00, 95% CI=1.05-3.83) and MM homozygotes of I199M (OR=1.81, 95% CI=0.95-3.54) in schizophrenic patients as compared to control subjects. When subjects were divided by gender, the association is specifically with female patients (OR=2.94 for RR and OR=2.7 for MM), but not with male patients. Our results indicate that the PAWR gene is associated with schizophrenia in our population, and this study provides genetic evidence to support the dopamine hypothesis of schizophrenia.

Association study of polymorphisms in the mitochondrial aspartate/glutamate carrier SLC25A12 (aralar) gene with schizophrenia.

Aralar is a mitochondrial calcium-regulated aspartate-glutamate carrier mainly distributed in brain and skeletal muscle, and involved in the transport of aspartate from mitochondria to the cytosol of a cell. Studies have shown that the brain N-acetyl aspartate (NAA) levels are greatly decreased in aralar-deficient mice, suggesting that aralar plays an important role in the synthesis of NAA in neuronal cells. Since magnetic resonance spectroscopy studies have revealed consistently reduced NAA levels in various brain regions of schizophrenic patients and their unaffected relatives, genes that affect aralar levels or NAA metabolism in the brain may be implicated in the pathogenesis of schizophrenia. Aralar is encoded by the SLC25A12 gene. In the past this gene has been found to be associated with susceptibility to autism; in this study we tested the hypothesis that SLC25A12 genetic variants confer susceptibility to schizophrenia. Six SLC25A12 polymorphisms were studied in a sample population of 253 people with schizophrenia and 216 normal controls. Significant linkage disequilibrium was obtained among the six polymorphisms. However, neither single marker nor haplotype analysis revealed an association between variants at the SLC25A12 locus and schizophrenia, suggesting that it is unlikely that the SLC25A12 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further studies with SLC25A12 variants relating to brain NAA levels in patients with schizophrenia are suggested.

No association of GRIP1 gene polymorphisms with schizophrenia in Chinese population.

Disturbance in glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. Since glutamate receptor interacting protein 1 (GRIP1), a modular protein that enables anchoring of AMPA receptors via its PDZ (postsynaptic density-95/discs large/zona occludens-1) domain and modulates d-serine release, plays an important role in glutamatergic function, this study tests the hypothesis that GRIP1 genetic variants confer susceptibility to schizophrenia. This study investigated whether GRIP1 genetic polymorphisms (rs1038923 and rs4913301) cause a predisposal to schizophrenia. Two GRIP1 polymorphisms were studied in a sample population of 252 people with schizophrenia and 207 normal controls. Significant linkage disequilibrium was obtained between the two polymorphisms. Results demonstrated that neither single marker nor haplotype analysis revealed an association between variants at the GRIP1 locus and schizophrenia, suggesting that it is unlikely that the GRIP1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia. However, association between schizophrenia and other polymorphisms in the GRIP1 gene cannot be totally ruled out as the whole gene was not covered by the two polymorphisms studied.

Association analysis of polymorphisms in the N-methyl-D-aspartate (NMDA) receptor subunit 2B (GRIN2B) gene and tardive dyskinesia in schizophrenia.

Tardive dyskinesia (TD) is a neurological disorder characterized by irregular, non-rhythmic, choreoathetotic and involuntary movements in single or multiple body regions. Chronic administration of typical antipsychotic agents, which predominantly act on dopamine receptors, implicates the dopamine system in susceptibility to TD. An alternative to this dopaminergic supersensivity hypothesis in understanding the pathogenesis of TD is the glutamatergic neurotoxicity hypothesis, which implicates the N-methyl-D-aspartate (NMDA) receptor in TD pathogenesis. In the present study, the association between three polymorphisms (T-200G, C366G and C2664T) of the GRIN2B gene, which encodes the 2B subunit of the NMDA receptor, and the occurrence and severity of TD were investigated in 273 Chinese schizophrenic patients receiving long-term antipsychotic treatment (TD: 142, non-TD: 133). There was no significant association between patients' genotype and allele frequencies and TD occurrence. Among the TD patients, the differences in the total scores on the Abnormal Involuntary Movement Scale (AIMS) among the three genotypes of each polymorphism were not significant. Because the three studied markers are in weak linkage disequilibrium with each other, haplotype-based association was not carried out. We conclude that genetic variations in the human GRIN2B gene probably do not play a major role in susceptibility to, or severity of TD.

Distribution of androgen receptor CAG repeat polymorphism in Chinese schizophrenia and its correlation with age at onset.

The action of androgens is mediated by the androgen receptors (ARs), which are located throughout the brain. The AR gene is implicated in the pathogenesis of schizophrenia because male siblings with schizophrenia share alleles at this gene at a rate higher than chance predicts, and differences in sex hormone function may explain the gender difference in schizophrenic manifestations. Since the shorter alleles of the AR CAG repeat polymorphism are associated with increased gene expression, we tested the hypothesis that the AR CAG repeat variant confers susceptibility to schizophrenia using a sample of 225 people with schizophrenia and 247 normal controls. Using the median AR repeat length in the normal group as the arbitrary cut-off point (<24 and >25 CAG repeats), the results show no association between the AR repeat length and schizophrenia in either sex. Furthermore. AR CAG repeat length did not affect the age of symptom onset in the schizophrenic population. Our findings suggest that it is unlikely that the AR CAG repeat polymorphism plays a major role in the pathogenesis of schizophrenia. Nevertheless, given that androgens affect cognitive function, violent behavior and mood, the effect of the AR CAG polymorphism on the clinical manifestations of schizophrenia may warrant further exploration.

Association study of androgen receptor CAG repeat polymorphism and male violent criminal activity.

Androgens exert their effects primarily by stimulating androgen receptors (ARs) and androgen activity has been implicated in antisocial or violent criminal behaviour. Exon 1 of the AR gene contains a highly polymorphic glutamine (CAG) repeat sequence. We tested the hypothesis that shorter AR CAG repeat polymorphisms, which have a greater AR gene expression, are related to violent criminal activity in Chinese males using a sample of 146 extremely violent criminals and 108 normal controls. The results show no association between the AR repeat length and violent convicts, although we found that there are more violent-criminal cases than control cases with the shorter (<17) AR gene trinucleotide repeat polymorphisms (7.5% vs. 1.9%; P=0.047). No correlation was found between the AR CAG repeat length and the first criminal record age in the violent-criminal group. The mean AR repeat length is not significantly different between substance dependence cases and antisocial personality disorder diagnosis in the violent criminals and normal controls. Our findings suggest that the AR CAG repeat polymorphism does not play a major role in the susceptibility of male violent criminal activity.

Polymorphisms in glycine transporter with schizophrenia.

Glycine acts as an obligatory co-agonist with glutamate on N-methyl-D-aspartate (NMDA) receptors. Brain glycine availability is determined by glycine transporters (GlyT1 or SLC6A9), which mediate glycine reuptake into nerve terminals. Since hypofunction of NMDA receptors has been implicated in the pathophysiology of schizophrenia, this study tests the hypothesis that GlyT1 genetic variants confer susceptibility to schizophrenia. Four GlyT1 polymorphisms were studied in a sample population of 249 people with schizophrenia and 210 normal controls. One polymorphism (rs16831541) was not informative in our Chinese population while the other three polymorphisms (rs1766967, rs2248632 and rs2248253) were analysed with chi-square tests and haplotype analysis. Significant linkage disequilibrium was obtained among the three polymorphisms. Neither single marker nor haplotype analysis revealed an association between variants at the GlyT1 locus and schizophrenia, suggesting that it is unlikely that the GlyT1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further studies with other GIyT1 variants, relating either to schizophrenia, psychotic symptoms or to therapeutic response in schizophrenia, are suggested.

Genetic signatures of heroin addiction.

Heroin addiction is a complex psychiatric disorder with a chronic course and a high relapse rate, which results from the interaction between genetic and environmental factors. Heroin addiction has a substantial heritability in its etiology; hence, identification of individuals with a high genetic propensity to heroin addiction may help prevent the occurrence and relapse of heroin addiction and its complications. The study aimed to identify a small set of genetic signatures that may reliably predict the individuals with a high genetic propensity to heroin addiction. We first measured the transcript level of 13 genes (RASA1, PRKCB, PDK1, JUN, CEBPG, CD74, CEBPB, AUTS2, ENO2, IMPDH2, HAT1, MBD1, and RGS3) in lymphoblastoid cell lines in a sample of 124 male heroin addicts and 124 male control subjects using real-time quantitative PCR. Seven genes (PRKCB, PDK1, JUN, CEBPG, CEBPB, ENO2, and HAT1) showed significant differential expression between the 2 groups. Further analysis using 3 statistical methods including logistic regression analysis, support vector machine learning analysis, and a computer software BIASLESS revealed that a set of 4 genes (JUN, CEBPB, PRKCB, ENO2, or CEBPG) could predict the diagnosis of heroin addiction with the accuracy rate around 85% in our dataset. Our findings support the idea that it is possible to identify genetic signatures of heroin addiction using a small set of expressed genes. However, the study can only be considered as a proof-of-concept study. As the establishment of lymphoblastoid cell line is a laborious and lengthy process, it would be more practical in clinical settings to identify genetic signatures for heroin addiction directly from peripheral blood cells in the future study.

A study of the association of (Val66Met) polymorphism in the brain-derived neurotrophic factor gene with alcohol dependence and extreme violence in Chinese males.

From studies of genetic-knockout animals, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth-factor family, has been implicated in both alcohol preference and aggressive behaviour. To test whether a BDNF genetic variant may be associated with alcohol-dependent and violent behaviours, we studied Val66Met polymorphism of the BDNF-gene in 110 cases of alcohol-dependence, in 134 extremely violent convicts, and in 149 individuals without psychosis or mood disorders. We also examined the association of this polymorphism with antisocial personality disorder comorbidity in the extremely violent convicts. The results showed that the genotype and allele frequencies for Val66Met polymorphism at the BDNF-gene site did not differ among the three groups. Furthermore, it was not demonstrated that this polymorphism is associated with antisocial personality disorder comorbidity in the extremely violent convicts. Based on these findings, it seems reasonable to suggest that this BDNF-gene Val66Met polymorphism is unlikely to play a major role in the genetic susceptibility to the traits of alcohol-dependence or violence proneness.