Shiau Foon Tee

Linkage of schizophrenia with TPH2 and 5-HTR2A gene polymorphisms in the Malay population

The serotoninergic system has been implicated in the etiology of schizophrenia and other behavioral disorders. Association studies have focused on the tryptophan hydroxylase 2 gene (TPH2) and the 5-hydroxytryptamine receptor 2A gene (5-HTR2A). We genotyped two single-nucleotide polymorphisms, A1438G of 5-HTR2A and intronic rs1386494 of TPH2 in the Malay population, using a sample size of 289 schizophrenic patients and 130 healthy controls. We found a significant association of A1438G of 5-HTR2A with schizophrenia in Malays. On the other hand, TPH2 polymorphism was not associated with schizophrenia. This is the first genetic association study concerning schizophrenia in the Malay population.

Neuregulin-1 (NRG-1) and its susceptibility to schizophrenia: a case- control study and meta-analysis

Neuregulin-1 is widely investigated due to its hypothesised association with schizophrenia. Single-nucleotide polymorphisms rs764059, rs2954041 and rs3924999 were investigated (417 patients with schizophrenia and 429 controls). We failed to demonstrate a significant association between rs2954041 and rs3924999 with schizophrenia in the three ethnic groups studied (Malay, Chinese, and Indian), while rs764059 was found to be monomorphic.

Meta-analysis of polymorphisms in TPH2 gene and suicidal behavior

The tryptophan hydroxylase-2 gene (TPH2) plays an important role in serotonin-related psychiatric disorders, including suicide. To date, the association of only one single-nucleotide polymorphism (SNP), rs1386494, of the TPH2 gene with suicide has been systematically reviewed (Schild et al., 2013). Therefore, we performed a meta-analysis to investigate associations between all published SNPs in the TPH2 gene and suicidal behavior. All articles pertaining to casecontrol studies in the PubMed database were screened. SNPs reported in less than 4 studies were excluded. Studies had to meet all of the following criteria: (1) be published in English; (2) contain independent data that are sufficient for calculation of the odds ratio (OR), confidence interval (CI) and P value; (3) report diagnostic methods; (4) report suicidal behavior, including suicide attempts, suicide completions and history of suicide attempts; and (5) include allele frequencies for were available for both suicide patients and controls. Studies that included and analyzed previously published data were excluded. Finally, a meta-analysis, which involved a total of 2536 cases and 3101 controls, was performed for nine TPH2 SNPs (rs4570625, rs7305115, rs1386486, rs11178997, rs1386493, rs1386494, rs1386495, rs10784941 and rs4290270) based on 11 case-control studies with 13 independent samples published between 1998 and 2013. Both the fixed (Mantel and Haenszel, 1959) and random effects (DerSimonian and Laird, 1986) models were applied for the pooled ORs and 95% CIs. The presence of heterogeneity was tested using Cochrans Q-test. If heterogeneity was confirmed, subgroup analyses were carried out. The results revealed rs7305115 was associated with suicidal behavior under a fixed effect model (Fig. 1). The analysis was retested by using the random effect framework due to a highly significant heterogeneity (I1⁄470.52%, P1⁄40.009). Nevertheless no association of suicidal behavior was detected. Rs4570625 and rs7305115 were subjected to subgroup analyses using a random effect model. Subgroup analyses that excluded subjects with comorbidities reduced the heterogeneity for rs4570625 (I1⁄440.38%, P1⁄40.152) and rs7305115 (I1⁄427.84%, P1⁄40.232). The summary OR for rs4570625 was 0.974 (P1⁄40.790, 95% CI1⁄40.802–1.128) and the same association was found for rs7305115 (OR1⁄40.985, P1⁄40.881, 95% CI1⁄40.811–1.197). An analysis for rs1386486 yielded a positive association when the fixed effect model was applied (Fig. 1). However, the summary OR was not statistically significant (OR1⁄40.835, P1⁄40.035, 95% CI1⁄40.706–0.987) when we applied random effect models. The tests of association between rs11178997, rs1386493, rs1386494, rs1386495, rs10784941 and rs4290270 and suicide yielded non-significant results (Fig. 1). We were able to perform meta-analyses based on nine SNPs in the TPH2 gene. Only two SNPs (rs7305115 and rs1386486) produced nominally significant results. However, the significant association between these two SNPs and suicide could not be replicated using the random effects model. High heterogeneity was mainly contributed by the controls with major depressive disorder and alcohol dependence. Interestingly, a strong association between rs7305115 and suicide was found in the major depressive disorder patients (Zhang et al., 2010). However, subgroup analysis using the major depressive disorder patients could not be performed based on a single study. Although the spectrum of suicidality is broad, studies of the effects of SNPs on specific subgroups are rare. The extreme rarity of such cases is the major limitation of the current study. Rs1386486, a quantitative allelic mRNA measurement in pons RNA (Lim et al., 2007), may be tagged with rs4290270, although this functional variant was found not significantly associated with suicide in this meta-analysis. To date, coverage of the genetic variants of TPH2 in suicide patients is low. It is impossible to conclude that the other SNPs do not have any significant contribution in the pathogenesis of suicide. Further studies are needed to support the associations of SNPs that are in partial linkage with functional variants within the TPH2 gene.

BDNF and DARPP-32 genes are not risk factors for schizophrenia in the Malay population.

A number of studies have pointed to the association of BDNF (brain-derived neurotrophic factor) and DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa) with schizophrenia. The purpose of this study was to determine whether these two genes are involved in the pathogenesis of schizophrenia in the Malay population. Two single nucleotide polymorphisms Val66Met of BDNF, -2036C>G and g.1238delG of DARPP-32 were genotyped in the Malay population in 200 patients with schizophrenia and 256 healthy controls. Analysis of allele and genotype frequencies in these two groups revealed no significant association of BDNF or DARPP-32 polymorphisms with schizophrenia in Malays. This is the first such association study in the Malay population.

Genetic Association of TCF4 and AKT1 Gene Variants with the Age at Onset of Schizophrenia

Background: Age at onset (AAO) is a known prognostic indicator for schizophrenia and is hypothesized to correlate with cognition and symptom severity. TCF4 and AKT1 are schizophrenia risk genes involved in cognitive functions. The current study examined the interactive effects of TCF4 and AKT1 variants with gender, family history of psychiatric disorders and ethnicity on the AAO of schizophrenia. Methods: This study consisted of 322 patients with schizophrenia meeting the DSM-IV criteria. Six single nucleotide polymorphisms (SNPs) of TCF4 (rs12966547, rs8766, rs2958182, rs9960767, rs10401120 and rs17512836) and seven AKT1 SNPs (rs2498804, rs3803304, rs2494732, rs3730358, rs1130214, rs2498784 and rs3803300) were genotyped using the TaqMan® SNP genotyping-based assays method. The relationship of AAO with each variant was investigated using analyses of covariance. Results: Among the TCF4 variants, rs12966547 (p = 0.024) and rs8766 (p = 0.021) were significantly associated with earlier AAO. We found a lower average AAO in patients with the AA genotype of rs12966547, while the CT genotype of rs8766 was demonstrated to have a protective effect on AAO. For rs8766, there was significant gene × gender interaction (p = 0.012) in influencing AAO. However, these results were not significant after false discovery rate correction. Significant gene × ethnicity interactions were observed to influence AAO (p < 0.05). The Kaplan-Meier curve of the minor AA genotype of rs12966547 displayed a significant trend (p = 0.008) for onset after 19 years of age. Similarly, the minor CC genotype of rs8766 showed a significantly (p = 0.034) lower AAO compared to the TT genotype. Conclusion: Our analyses suggest that individual risk genotypes may influence the risk of schizophrenia in an age-specific manner.

Genetic association of single nucleotide polymorphisms in dystrobrevin binding protein 1 gene with schizophrenia in a Malaysian population

Dystrobrevin binding protein 1 (DTNBP1) gene is pivotal in regulating the glutamatergic system. Genetic variants of the DTNBP1 affect cognition and thus may be particularly relevant to schizophrenia. We therefore evaluated the association of six single nucleotide polymorphisms (SNPs) with schizophrenia in a Malaysian population (171 cases; 171 controls). Associations between these six SNPs and schizophrenia were tested in two stages. Association signals with p < 0.05 and minor allele frequency > 0.05 in stage 1 were followed by genotyping the SNPs in a replication phase (stage 2). Genotyping was performed with sequenced specific primer (PCR-SSP) and restriction fragment length polymorphism (PCR-RFLP). In our sample, we found significant associations between rs2619522 (allele p = 0.002, OR = 1.902, 95%CI = 1.266 – 2.859; genotype p = 0.002) and rs2619528 (allele p = 0.008, OR = 1.606, 95%CI = 1.130 – 2.281; genotype p = 6.18 × 10−5) and schizophrenia. Given that these two SNPs may be associated with the pathophysiology of schizophrenia, further studies on the other DTNBP1 variants are warranted.

No evidence for association between DRD3 and COMT with schizophrenia in a Malay population.

Molecular components of the dopamine D3 receptor (DRD3) may play an important role in the pathophysiology of schizophrenia. Previous studies have demonstrated an association between DRD3 Ser9Gly and cathechol-o-methyltransferase (COMT, SNP = rs165656) polymorphisms and schizophrenia but the results were inconclusive. We investigated this apparent association between Ser9Gly (A/G) polymorphism and an intronic SNP (dbSNP or rs165656) in 261 Malay patients diagnosed with schizophrenia and 216 controls, using PCR-RFLP. The genotype distribution of the polymorphism DRD3 Ser9Gly was in Hardy-Weinberg equilibrium (HWE) for patients (P = 0.1251) and out of HWE for controls (P = 0.0137). However, both healthy controls and schizophrenia patients were out of HWE for the polymorphism COMT rs165656. Based on allele and genotype frequencies in both groups, we found no significant association of DRD3 Ser9Gly polymorphisms and COMT (rs165656) with schizophrenia in Malays. Further studies should examine the association between other dopamine-related genes and the behavioral phenotypes of schizophrenia.

COMT haplotype analyses in Malaysians with schizophrenia

The present study included a total 261 patients with schizophrenia and 261 healthy controls to replicate the genetic association between the cathechol-o-methyltransferase gene and schizophrenia using a haplotype block-based gene-tagging. The G-G-G haplotype was found to show a highly significant association with schizophrenia.

Assessment of Cognition in Schizophrenia Using Trail Making Test: A Meta-Analysis

Objective The present meta-analysis aimed to analyze the cognitive performance of schizophrenia patients measured by Trail Making Tests (TMT) and the contribution of socio-demographic factors to cognitive impairments. Methods PubMed and PsycARTICLES databases were searched for the studies published between January 1985 and November 2017. Data were drawn from 19 studies encompassing 1095 patients and 324 controls. The effect size and heterogeneity were assessed with Comprehensive Meta-Analysis version 2 using random-effect model. Results Overall, the results showed that the schizophrenia patients performed significantly (p<0.001) worse than healthy controls in both TMT-A and B. However, concurrent substance abuse, clinical status (inpatient or outpatient), duration of education and duration of illness were not associated with cognitive impairment among the schizophrenia patients. Conclusion The present meta-analysis confirmed the cognitive processing speed and flexibility of schizophrenia patients were impaired. However, their duration of education, duration of illness and clinical status (inpatient or outpatient) were not the risk factors.

Identification of AKT1 3′UTR variants in two Indian schizophrenia patients with poor executive functioning

Neurocognitive ability is a potential heritable phenotype for schizophrenia, with evidence of shared genetic aetiology between schizophrenia and cognitive impairment (Owens et al., 2011). The most important domains of cognition are working memory, attention, problem solving, and speed of processing. V-Akt murine thymoma viral oncogene homolog 1 (AKT1) plays a role in modulating synaptic plasticity and signal transduction pathways (Freyberg et al., 2010). Deficiency in AKT1 may lead to abnormal prefrontal cortical structure and deficits in cognitive functions (Lai et al., 2006). There is a lack of studies on functional variants at exonic and regulatory regions due to the difficulty in interpretation of their significance. Thus, we aimed to investigate these functional variants to identify their involvement in schizophrenia and cognitive impairment.