Yu-Chih Shen

Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients

OBJECTIVES Aripiprazole, a novel antipsychotic agent, acts as a partial agonist at dopamine D2 receptors (DRD2). We investigate whether its efficacy is predictable by DRD2/ANKK1 gene polymorphisms and clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. METHOD After hospitalization, the patients (n=128) were given aripiprazole for up to 4 weeks. They were genotyped for four functional DRD2/ANKK1 polymorphisms: -141 Ins/Del, Ser311Cys, C957T, and TaqIA. Clinical factors such as gender, age, illness duration, education level, diagnostic subtype, and medication dosage were also recorded. Psychopathology was measured biweekly with the positive and negative syndrome scale (PANSS). The effects of genetic and clinical factors on PANSS performance upon aripiprazole treatment were analyzed by a mixed modeling approach (SAS Proc MIXED). RESULTS Compared to the patients with TaqI A2/A2 genotype, A1 carriers are associated with superior therapeutic response on positive symptoms after 4-week aripiprazole treatment. Regarding the C957T polymorphism, patients with C/C genotype were associated with poor aripiprazole response for excitement symptoms when compared with T/T patients. The other two polymorphisms, -141 Ins/Del, and Ser311Cys, have no significant effects on PANSS performance. The clinical factors including medication dosage, illness duration, and diagnostic subtype could influence PANSS performance upon aripiprazole treatment. CONCLUSION This study suggests that DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole.

HTR2A A-1438G/T102C polymorphisms predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients

RationaleAripiprazole acts as a partial agonist at dopamine D2 and D3 and serotonin 1A receptors and as an antagonist at serotonin 2A receptors (HTR2A). Since aripiprazole acts as an antagonist at HTR2A, genetic variants of HTR2A may be important in explaining variability in response to aripiprazole.ObjectivesThis study investigated whether the efficacy of aripiprazole can be predicted by functional HTR2A A-1438G/T102C polymorphisms (rs63311/rs6313) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia.Materials and methodsAfter hospitalization, the patients (n = 128) were given a 4-week course of aripiprazole. Patients were genotyped for HTR2A A-1438G/T102C polymorphisms via the restriction fragment length polymorphism method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype, and medication dosage were noted as well. The researchers measured psychopathology biweekly, using the Positive and Negative Syndrome Scale (PANSS). A mixed model regression approach (SAS Proc MIXED) was used to analyze the effects of genetic and clinical factors on PANSS performance after aripiprazole treatment.ResultsWe found that the GG/CC genotype group of HTR2A A-1438G/T102C polymorphisms predicts poor aripiprazole response specifically for negative symptoms. In addition, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype, were found to influence PANSS performance after aripiprazole treatment.ConclusionsThe data suggest HTR2A A-1438G/T102C polymorphisms may predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients as modified by clinical factors.

Effects of the DRD3 Ser9Gly polymorphism on aripiprazole efficacy in schizophrenic patients as modified by clinical factors.

Aripiprazole, a novel antipsychotic agent, has a unique pharmacological action (partial agonist) on the dopamine neurotransmission system. Aripiprazole has high affinity for dopamine D2 and D3 receptors (DRD2 and DRD3). We investigated whether the efficacy of aripiprazole can be predicted by a functional DRD3 gene polymorphism Ser9Gly (rs6280) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n=128) were given aripiprazole for up to four weeks. Patients were genotyped for DRD3 Ser9Gly polymorphism by Restriction Fragment Length Polymorphism (RFLP) method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype and medication dosage were recorded. Psychopathology was measured biweekly with the Positive and Negative Syndrome Scale (PANSS). The effects of genetic and clinical factors on PANSS performance after aripiprazole treatment were analyzed by a mixed model regression approach (SAS Proc MIXED). We found that, although the Ser carriers have numerically larger score reductions when compared with non-carriers in almost all PANSS dimensions, the difference of their effects are statically not significant. However, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype could influence PANSS performance after aripiprazole treatment. This study suggests that DRD3 Ser9Gly polymorphism may not contribute significantly to inter-individual differences in therapeutic efficacy of aripiprazole, but some clinical factors may predict treatment efficacy.

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.

Resequencing and association study of the NFKB activating protein-like gene (NKAPL) in schizophrenia

OBJECTIVES Schizophrenia is a highly inheritable disorder, but many aspects of its etiology and pathophysiology remain poorly understood. Recently, in the Han Chinese population, a SNP rs1635 located within the exon of the NKAPL gene (encoding NFKB activating protein-like) achieved genome-wide significance in schizophrenia. METHODS In order to find the causal variants of the NKAPL gene in schizophrenia, we searched for genetic variants in the promoter region, and exons (including both UTR ends) using direct sequencing in a sample of patients with schizophrenia (n=515) and non-psychotic controls (n=456), all Han Chinese from Taiwan, and conducted an association and rudimentary functional study. RESULTS We identified 5 common SNPs (defined as minor allele frequency (MAF)>0.01) in the NKAPL gene. In a case-control association analysis, the minor allele (A) of rs1635 was significantly more common among patients than controls (P=0.0003, OR=1.41, 95% CI=1.17-1.71). A haplotype analysis of the 5 common SNPs indicated a risk haplotype (rs12000C-rs1635A-rs9461446C-rs3734564G-rs1679709G) associated with schizophrenia (P=2.77e-005, OR=1.53, 95% CI=1.25-1.87). In addition, we identified 4 patient-specific rare SNPs (MAF<0.01) (c.137G>A, c.213G>A, c.752C>T (rs370337122), and c.844G>A (rs147161729)) within the NKAPL gene. In silico analysis demonstrated their functional impact on the protein; however, there was also 1 control-specific rare SNP (c.119G>A) detected within the NKAPL gene, indicating that the clinical relevance of these putatively pathological rare SNPs is not straightforward. CONCLUSIONS This study suggested that rs1635 in the NKAPL gene appeared to play a role in conferring susceptibility to schizophrenia. In addition, some rare SNPs in the NKAPL gene with possibly damaging effects may be important in our patients. Our study provides genetic clues to indicate the involvement of NKAPL in schizophrenia.

Resequencing of the vesicular glutamate transporter 2 gene (VGLUT2) reveals some rare genetic variants that may increase the genetic burden in schizophrenia

OBJECTIVES Vesicular glutamate transporters (VGLUT1-3) package glutamate into vesicles in the presynaptic terminal and regulate the release of glutamate. In mesencephalic dopamine neuron culture, the majority of isolated dopamine neurons express VGLUT2, but not VGLUT1 or 3, have been demonstrated. As related to the dysregulated glutamatergic hypothesis of schizophrenia, the gene encoding VGLUT2 is the most plausible candidate involved in the pathogenesis of this illness. METHODS We searched for genetic variants in the promoter region and 12 exons (including UTR ends) of the VGLUT2 gene using direct sequencing in a sample of Han Chinese schizophrenic patients (n=375) and non-psychotic controls (n=366) from Taiwan, and conducted a case-control association study. RESULTS We identified 8 common SNPs in the VGLUT2 gene. SNP and haplotype-based analyses showed no association with schizophrenia. Besides, we identified 9 rare variants in 13 out of 375 patients, including 3 variants located at the promoter region, 2 synonymous variants located at protein coding regions, and 4 variants located at UTR ends. No rare variants were found in the control subjects. Collectively, these rare variants were significantly overrepresented in the patient group (3.5% versus 0, p value of Fishers exact test=2.3x10(-5)), suggesting they may contribute to the pathogenesis of schizophrenia. CONCLUSION Although the functional significance of these rare variants remains to be characterized, our study may lend support to the multiple rare mutations hypothesis of schizophrenia, and may provide genetic clues to indicate the involvement of the glutamate transmission pathway in the pathogenesis of schizophrenia.

Genetic and functional analysis of the gene encoding GAP-43 in schizophrenia

OBJECTIVES In earlier reports, growth-associated protein 43 (GAP-43) has been shown to be critical for initial establishment or reorganization of synaptic connections, a process thought to be disrupted in schizophrenia. Additionally, abnormal GAP-43 expression in different brain regions has been linked to this disorder in postmortem brain studies. In this study, we investigated the involvement of the gene encoding GAP-43 in the susceptibility to schizophrenia. METHODS We searched for genetic variants in the promoter region and 3 exons (including both UTR ends) of the GAP-43 gene using direct sequencing in a sample of patients with schizophrenia (n=586) and non-psychotic controls (n=576), both being Han Chinese from Taiwan, and conducted an association and functional study. RESULTS We identified 11 common polymorphisms in the GAP-43 gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. Additionally, we identified 4 rare variants in 5 out of 586 patients, including 1 variant located at the promoter region (c.-258-4722G>T) and 1 synonymous (V110V) and 2 missense (G150R and P188L) variants located at exon 2. No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated that the regulatory activity of construct containing c.-258-4722T was significantly lower as compared to the wild type construct (c.-258-4722G; p<0.001). In silico analysis also demonstrated the functional relevance of other rare variants. CONCLUSIONS Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and it provides genetic clues that indicate the involvement of GAP-43 in this disorder.

Schizophrenia is associated with an increased risk of sexually transmitted infections: A nationwide population-based cohort study in Taiwan

OBJECTIVES In Taiwan, there has been a growing emphasis on physical health screening, health education and improving access to treatment in patients with schizophrenia (SCZ). However, sexual health needs, including screening and prevention of sexually transmitted infections (STI), are neglected in this population. The study aimed to investigate the association between SCZ and the subsequent incident STI and to examine potential risk factors. METHODS Using the National Health Insurance Research Database of Taiwan, 58,948 SCZ patients and 235,784 controls matched by gender and age were enrolled between 2000 and 2010 and followed until the end of 2011. Participants who developed any STI (HIV, syphilis, genital warts, gonorrhea, chlamydial infection, and trichomoniasis) during the follow-up period were identified. Cox regression analysis was performed to examine the risk of STI between SCZ patients and controls. RESULTS SCZ patients were predisposed to developing STI (hazard ratio (HR): 1.11, 95% confidence interval (95% CI): 1.01-1.21) that could be caused by syphilis (HR: 2.58, 95% CI: 2.14-3.10) or possibly HIV (Crude HR: 1.39, 95% CI: 1.04-1.86; adjusted HR: 1.11, 95% CI: 0.81-1.52). Additionally, this study found that female, young adults, low-income, living in less urbanized areas, and comorbid substance abuse were potential risk factors for developing STI. CONCLUSION This study shows that SCZ is associated with an increased risk of developing STI, which has direct implications for the development of targeted prevention interventions or regular sexual health screening in mental health clinics to reduce the disproportionate burden of HIV and other STI in SCZ patients.