I-Ching Lai

Polymorphism of the adrenergic receptor alpha 2a −1291C>G genetic variation and clozapine-induced weight gain

Summary.Weight gain, leading to further morbidity and poor treatment compliance, is a common consequence of treatment with clozapine. The substantial interindividual and interracial differences in drug-induced weight gain suggest that genetic factors may be important. Several studies showed that alpha-2, adrenoceptor may related to feeding behavior with rat or lipolytic activity of human adipocyte tissue, they are related to body weight change. In the study, we try to test the possible relation of clozapine-induced weight gain and adrenergic receptor alpha 2a −1291C>G genetic polymorphism in a long term follow up (14.0 ± 6.2 months). Our results show the genotype GG (8.45 ± 7.2 Kg) with higher mean body weight gain than genotype CC (2.79 ± 6.1 Kg) (p = 0.023). The finding identify a genetic factor associated with clozapine-induced weight gain in schizophrenic patients.

Negative association between Catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and persistent tardive dyskinesia in schizophrenia

Summary.Chronic administration of typical antipsychotic agents, which mainly act on the dopamine receptors, implicates a role of dopamine system on the susceptibility of tardive dyskinesia (TD). In the present study, the association between a functional Val158Met polymorphism of Catechol-O-methyltransferase (COMT) gene and TD occurrence and TD severity was investigated in 299 Chinese schizophrenic patients with long-term antipsychotic treatment (TD: 166, non-TD: 133). After adjusting the effects of confounding factors, there was no significant association between COMT genotype and TD occurrence (p=0.367). Among TD patients, we found no significant correlation between COMT genotypes and the total scores of abnormal involuntary movement scale (AIMS) (p=0.629). We concluded that this COMT polymorphism might not play a major role in the susceptibility of TD nor on the severity of TD.

Genetic association between TNF-α −308 G>A polymorphism and longitudinal weight change during clozapine treatment

The aim of the study was to investigate the association between genetic variation in the tumor necrosis factor‐alpha (TNF‐α) gene and longitudinal weight change during long‐term clozapine treatment.

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 D2 dopamine receptors (D2DR) and produce D2DR supersensitivity. On contrary, regulators of G‐protein signaling (RGS) can enhance the signal termination of G‐protein‐coupled D2DR. 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.

The coding‐synonymous polymorphism rs1045280 (Ser280Ser) in β‐arrestin 2 (ARRB2) gene is associated with tardive dyskinesia in Chinese patients with schizophrenia

Background:  Tardive dyskinesia (TD) is a severe and potentially irreversible adverse effect of long‐term antipsychotic treatment. Typical antipsychotics are commonly binding to the dopamine receptor D2 (DRD2), but the occurrence of antipsychotic‐induced TD is rather delayed; therefore, the development of TD may be associated with mediators or signalling complexes behind DRD2, such as β‐arrestin 2 (ARRB2), an important mediator between DRD2 and serine–threonine protein kinase (AKT) signal cascade.

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

BackgroundDyskinesia 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.MethodsIn 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.ResultsGenotype 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).ConclusionOur 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.

Support for the involvement of the ERBB4 gene in schizophrenia: a genetic association analysis.

Cellular, animal and human studies support the involvement of aberrant NRG-ErbB signaling in the pathogenesis of schizophrenia. The aim of the present study was to examine whether genetic variation in the human ERBB4 gene is associated with susceptibility to schizophrenia. Two hundred and twenty-seven unrelated chronic inpatients with schizophrenia were enrolled in the study, and the genetic variation in the polymorphisms of the ERBB4 gene in the patients was compared with that of the control group, which consisted of 223 subjects free of psychiatric illness. The results showed that one coding-synonymous polymorphism (rs3748962, Val1065Val) was in genotypic (p=0.0027) and allelic (p=0.0007) association with schizophrenia. In comparison with subjects of the rs3748962-TT type, those of the rs3748962-CT and rs3748962-CC types were at 1.74- and 2.64-fold greater risk of schizophrenia (CT vs. TT: OR=1.71 (95% CI=1.15-2.53), p=0.0014; CC vs. TT: OR=2.64 (95% CI=1.37-5.23), p=0.0047), which supports the hypothesis of an additive model of transmission (p=0.0006). Furthermore, the frequency of haplotype ATC of rs3791709-rs2289086-rs3748962 was found to be significantly higher in the patients with schizophrenia than in the controls (case vs. control=36.0% vs. 24.4%, permutation p-value=0.0002). The findings support the involvement of the ERBB4 gene in schizophrenia in Han Chinese.

Analysis of genetic variations in the human melatonin receptor (MTNR1A, MTNR1B) genes and antipsychotics-induced tardive dyskinesia in schizophrenia

Abstract Objectives. Antipsychotics-induced tardive dyskinesia (TD) has been suggested to be related to altered dopaminergic neurotransmission in the striatum. Melatonin has a modulating effect on dopaminergic neurotransmission in the brain; therefore, the hypothesis of an association between the melatonin receptor genes (MTNR1A, MTNR1B) and antipsychotics-induced TD was examined in this study. Methods. Schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale, and only patients who were either free of any abnormal involuntary movement (non-TD group) or who demonstrated persistent TD (TD group) were enrolled. Genotyping of six tagging single nucleus polymorphisms (SNPs) in the melatonin receptor genes (MRNR1A, MTNR1B) was then performed for each subject. Results. Four hundred and eighteen inpatients (TD=256, non-TD=162) fitted the study criteria and underwent TD assessment and genotyping. Individual haplotype analysis showed that the haplotype ATG was significantly associated with non-TD (permutation P=0.037), and the association was also found to be significant by global haplotype analyses (permutation P=0.045). Conclusions. Our results indicated a significant association between the haplotype ATG in the MTNR1A gene and non-TD. Further replication in other countries or other populations is indicated.

Exomic sequencing of the glutamate receptor, ionotropic, N-methyl-d-aspartate 3A gene (GRIN3A) reveals no association with schizophrenia

BACKGROUND Growing evidence suggests that dysregulation of N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate neurotransmission may be involved in the pathophysiology of schizophrenia. The NMDAR is a heteromeric protein complex consisting of subunits from three subfamilies (NR1, NR2A, 2B, 2C, 2D and NR3A, 3B). The unique ability of NR3A to modulate the NMDAR function makes it an attractive candidate gene of schizophrenia. The purpose of this study was to investigate the involvement of the gene encoding the human NR3A subunit (GRIN3A) in the liability to schizophrenia. METHODS We searched for genetic variants in the putative core promoter region and all the exons (including UTR ends) of the GRIN3A gene in 333 Han Chinese patients with schizophrenia and 369 control subjects from Taiwan using direct polymerase chain reaction (PCR) autosequencing, and assessed their association with schizophrenia. RESULTS We identified 22 single nucleotide polymorphisms (SNPs) in the GRIN3A gene in this sample. SNP- and haplotype-based analyses showed no association of these 22 SNPs with schizophrenia. Nevertheless, we identified two missense mutations (D133N and Q1091H), one nonsense mutation (R1024X), and two synonymous mutations (Y873Y and E889E) of the GRIN3A gene in 6 out of 333 (1.8%) patients, while no rare mutations were found in 369 control subjects (p=0.011, Fishers exact test, one-tailed). In silico analysis showed that the R1024X and Q1091H mutations are possibly damaging. CONCLUSIONS Although the functional significance of these mutations remains to be characterized, our study indicates that rare mutations in the GRIN3A gene may contribute to the pathogenesis of schizophrenia in certain patients.

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.