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Genetic Association Analysis of Dopamine DRD3 Ser9Gly Polymorphism and Schizophrenia in Malay Population

Tee S, Tang P, Loh H

Iran J Public Health, 2011;40(2):6-10.
PMID: 23113067

BACKGROUND: Molecular components of the dopamine receptor (DRD3) play an important role in the pathophysiology of schizophrenia (SCZ). Previous studies have demonstrated an association between the DRD3 Ser9Gly polymorphism and SCZ but the results have been inconclusive.
METHOD: In this study, we investigated this controversial association between the Ser9Gly (A/G) polymorphism and SCZ using Malay cases-control (261 cases/157 controls) samples. PCR-RFLP was performed to genotype the distribution of the DRD3 Ser9Gly polymorphism.
RESULTS: Both healthy control and SCHZ patient groups were in of Hardy-Weinberg equilibrium for the analyzed genetic variability. There was a significant association between the genotype distribution DRD3 polymorphisms and SCZ (χ(2)= 9.359; df = 2; P = 0.009).
CONCLUSION: We believe that further studies are required to examine the association between others dopamine-related genes and the behavioral phenotypes of SCZ.
Fulltext No evidence for association between DRD3 and COMT with schizophrenia in a Malay population

Tee SF, Tang PY, Loh HC

Genet. Mol. Res., 2011;10(3):1850-5.
PMID: 21948748 DOI: 10.4238/vol10-3gmr1237

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

Tee SF, Tang PY, Loh HC

Psychiatry Res, 2012 Jan 30;195(1-2):83-4.
PMID: 21872942 DOI: 10.1016/j.psychres.2011.07.039

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

Tee SF, Chow TJ, Tang PY, Loh HC

Genet. Mol. Res., 2010;9(3):1274-8.
PMID: 20623453 DOI: 10.4238/vol9-3gmr789

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.
Fulltext Traditional Chinese Medicine Body Constitutions and Psychological Determinants of Depression among University Students in Malaysia: A Pilot Study

Yap SY, Foo CN, Lim YM, Ng FL, Mohd-Sidik S, Tang PY, et al.

Int J Environ Res Public Health, 2021 May 18;18(10).
PMID: 34069915 DOI: 10.3390/ijerph18105366

Depression is commonly observed in university students, who are a high risk group for developing psychiatric disorders during adulthood. This study aimed to determine the prevalence of depression and its traditional Chinese medicine body constitutions and psychological determinants among university students in Malaysia. A cross-sectional pilot study was conducted between 9 and 28 September 2020 among 80 university students in Malaysia. Participants completed online survey questionnaires, including the validated Patient Health Questionnaire (PHQ-9), Constitution in Chinese Medicine Questionnaire (CMCQ), Dysfunctional Attitude Scale (DAS), Depression Anxiety Stress Scale (DASS-21) stress subscale, Perceived Stress Scale (PSS-10), and Rosenberg Self-Esteem Scale (RSES), which assess depression, body constitution, dysfunctional attitude, stress, perceived stress, and self-esteem. Multiple linear regression analyses were performed to determine the associated risk factors for depression. The overall prevalence of depression among university students was 33.8%. The multiple regression analysis showed a significant relationship between depression and qi-stagnation constitution (B = 0.089, p = 0.011), balanced constitution (B = -0.077, p = 0.049), and self-esteem (B = -0.325, p = 0.001). Our findings suggest that some traditional Chinese medicine body constitutions and self-esteem are significant risk factors affecting depression among university students. Identifying risk factors of depression is vital to aid in the early detection of depression among university students.
Fulltext BDNF and DARPP-32 genes are not risk factors for schizophrenia in the Malay population

Loh HC, Tang PY, Tee SF, Chow TJ, Cheah YC, Singh SS

Genet. Mol. Res., 2012;11(1):725-30.
PMID: 22576830 DOI: 10.4238/2012.March.22.2

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.
Editorial: The link between nutrition and schizophrenia

Tang PY, Tee SF, Su KP

Front Psychiatry, 2022;13:1074120.
PMID: 36479557 DOI: 10.3389/fpsyt.2022.1074120
Synchronous papillary thyroid carcinoma and medullary thyroid carcinoma - a pitfall waiting to happen

Tang PY, Khor LY, Takano A

Malays J Pathol, 2017 Aug;39(2):171-174.
PMID: 28866700

Papillary thyroid carcinoma (PTC) is the most common thyroid carcinoma and is derived from thyroid follicular cells. In contrast, medullary thyroid carcinoma (MTC) is rare and originates from the parafollicular C-cells. Synchronous occurrence of these two carcinomas is uncommon and occurs as either discrete lesions or as a mixed lesion. The current case report describes a 50-year-old woman with synchronous multiple discrete MTC and PTC with lymph nodes metastasis. Pathologists and treating physicians should be aware of the synchronous coexistence of these entities to avoid possible misdiagnosis.
Meta-analysis of polymorphisms in TPH2 gene and suicidal behavior

Choong MY, Tee SF, Tang PY

Psychiatry Res, 2014 Dec 30;220(3):1163-6.
PMID: 25219619 DOI: 10.1016/j.psychres.2014.07.076
Evaluation of carotenoid level in schizophrenic patients using non-invasive measurement

Chow TJ, Loh HC, Tee SF, Tang PY

Asian J Psychiatr, 2010 Dec;3(4):190-3.
PMID: 23050886 DOI: 10.1016/j.ajp.2010.09.006

Free radicals are produced as part of the body immune response triggered by exogenous oxidants. In excess, they impair antioxidant defence system and cause oxidative stress. Antioxidants are hypothesised as antidotes to counteract oxidative stress and improve immune function. Carotenoids serve as a reliable indicator of overall antioxidant level in humans. This study investigated the possible relationship of carotenoid antioxidant levels in schizophrenia. A total of 351 schizophrenic subjects from Hospital Bahagia Ulu Kinta, Malaysia and 247 healthy controls were recruited. Subjects' skin carotenoid levels were measured using a non-invasive technique, Raman spectroscopy. The results showed significant (P<0.01) reduction of carotenoid level in patient compared to healthy controls, suggesting higher levels of oxidative stress in schizophrenia. Comparison between gender, age, subtypes, antipsychotic drug treatments, and duration of illness was investigated, but none was significantly associated with carotenoid score. Antipsychotics were suggested to be the possible causes of reduced antioxidant level in schizophrenia.
Genetic Association of TCF4 and AKT1 Gene Variants with the Age at Onset of Schizophrenia

Chow TJ, Tee SF, Yong HS, Tang PY

Neuropsychobiology, 2016;73(4):233-240.
PMID: 27305091

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

Tan GK, Tee SF, Tang PY

Genet Mol Biol, 2015 May;38(2):138-46.
PMID: 26273215 DOI: 10.1590/S1415-4757382220140142

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

Chow TJ, Tee SF, Loh SY, Yong HS, Abu Bakar AK, Song SL, et al.

Asian J Psychiatr, 2018 Aug;36:17-18.
PMID: 29864676 DOI: 10.1016/j.ajp.2018.05.025
Variants in ZNF804A and DTNBP1 assessed for cognitive impairment in schizophrenia using a multiplex family-based approach

Chow TJ, Tee SF, Loh SY, Yong HS, Abu Bakar AK, Tang PY

Psychiatry Res, 2018 12;270:1166-1167.
PMID: 29754893 DOI: 10.1016/j.psychres.2018.04.051
Association of functional polymorphisms in 3'-untranslated regions of COMT, DISC1, and DTNBP1 with schizophrenia: a meta-analysis

Mohamed ZI, Tee SF, Tang PY

Psychiatr Genet, 2018 12;28(6):110-119.
PMID: 30252773 DOI: 10.1097/YPG.0000000000000210

INTRODUCTION: In recent years, various studies have accumulated evidence of the involvement of single nucleotide polymorphisms (SNPs) in introns and exons in schizophrenia. The association of functional SNPs in the 3'-untranslated regions with schizophrenia has been explored in a number of studies, but the results are inconclusive because of limited meta-analyses. To systematically analyze the association between SNPs in 3'-untranslated regions and schizophrenia, we conducted a meta-analysis by combining all available studies on schizophrenia candidate genes.
MATERIALS AND METHODS: We searched candidate genes from the schizophrenia database and performed a comprehensive meta-analysis using all the available data up to August 2017. The association between susceptible SNPs and schizophrenia was assessed by the pooled odds ratio with 95% confidence interval using fixed-effect and random-effect models.
RESULTS: A total of 21 studies including 8291 cases and 9638 controls were used for meta-analysis. Three investigated SNPs were rs165599, rs3737597, and rs1047631 of COMT, DISC1, and DTNBP1, respectively. Our results suggested that rs3737597 showed a significant association with schizophrenia in Europeans (odds ratio: 1.584, P: 0.002, 95% confidence interval: 1.176-2.134) under a random-effect framework.
CONCLUSION: This meta-analysis indicated that rs3737597 of DISC1 was significantly associated with schizophrenia in Europeans, and it can be suggested as an ethnic-specific risk genetic factor.
Analysis of variants of AKT1 in schizophrenia multiplex families

Chow TJ, Tee SF, Loh SY, Yong HS, Abu Bakar AK, Tang PY

Asian J Psychiatr, 2020 Mar;49:101957.
PMID: 32078952 DOI: 10.1016/j.ajp.2020.101957
Functional characterization of two variants in the 3'-untranslated region (UTR) of transcription factor 4 gene and their association with schizophrenia in sib-pairs from multiplex families

Mohamed ZI, Tee SF, Chow TJ, Loh SY, Yong HS, Bakar AKA, et al.

Asian J Psychiatr, 2019 Feb;40:76-81.
PMID: 30771755 DOI: 10.1016/j.ajp.2019.02.001

Transcription factor 4 (TCF4) gene plays an important role in nervous system development and it always associated with the risk of schizophrenia. Since miRNAs regulate targetgenes by binding to 3'UTRs of target mRNAs, the functional variants located in 3'UTR of TCF4 are highly suggested to affect the gene expressions in schizophrenia. To test the hypothesis regarding the effects of the variants located in 3'UTR of TCF4, we conducted an in silico analysis to identify the functional variants and their predicted functions. In this study, we sequenced the 3'UTR of TCF4 in 13 multiplex schizophrenia families and 14 control families. We found two functional variants carried by three unrelated patients. We determined that the C allele of rs1272363 and the TC insert of rs373174214 might suppress post- transcriptional expression. Secondly, we cloned the region that flanked these two variants into a dual luciferase reporter system and compared the luciferase activities between the pmirGLO-TCF4 (control), pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263. Both pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263 caused lower reporter gene activities, as compared to the control. However, only the C allele of rs1272363 reduced the luciferase activity significantly (p = 0.0231). Our results suggested that rs1273263 is a potential regulator of TCF4 expression, and might be associated with schizophrenia.
Fulltext Integrative Roles of Dopamine Pathway and Calcium Channels Reveal a Link between Schizophrenia and Opioid Use Disorder

Thiagarajan SK, Mok SY, Ogawa S, Parhar IS, Tang PY

Int J Mol Sci, 2023 Feb 17;24(4).
PMID: 36835497 DOI: 10.3390/ijms24044088

Several theories have been proposed to explain the mechanisms of substance use in schizophrenia. Brain neurons pose a potential to provide novel insights into the association between opioid addiction, withdrawal, and schizophrenia. Thus, we exposed zebrafish larvae at 2 days post-fertilization (dpf) to domperidone (DPM) and morphine, followed by morphine withdrawal. Drug-induced locomotion and social preference were assessed, while the level of dopamine and the number of dopaminergic neurons were quantified. In the brain tissue, the expression levels of genes associated with schizophrenia were measured. The effects of DMP and morphine were compared to vehicle control and MK-801, a positive control to mimic schizophrenia. Gene expression analysis revealed that α1C, α1Sa, α1Aa, drd2a, and th1 were up-regulated after 10 days of exposure to DMP and morphine, while th2 was down-regulated. These two drugs also increased the number of positive dopaminergic neurons and the total dopamine level but reduced the locomotion and social preference. The termination of morphine exposure led to the up-regulation of th2, drd2a, and c-fos during the withdrawal phase. Our integrated data implicate that the dopamine system plays a key role in the deficits in social behavior and locomotion that are common in the schizophrenia-like symptoms and opioid dependence.
Fulltext Assessment of Cognition in Schizophrenia Using Trail Making Test: A Meta-Analysis

Laere E, Tee SF, Tang PY

Psychiatry Investig, 2018 Oct;15(10):945-955.
PMID: 30223641 DOI: 10.30773/pi.2018.07.22

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.
Fulltext 8-Hydroxy-2'-Deoxyguanosine and Reactive Oxygen Species as Biomarkers of Oxidative Stress in Mental Illnesses: A Meta-Analysis

Goh XX, Tang PY, Tee SF

Psychiatry Investig, 2021 Jul;18(7):603-618.
PMID: 34340273 DOI: 10.30773/pi.2020.0417

OBJECTIVE: Mental illnesses may be caused by genetic and environmental factors. Recent studies reported that mental illnesses were accompanied by higher oxidative stress level. However, the results were inconsistent. Thus, present meta-analysis aimed to analyse the association between oxidative DNA damage indicated by 8-hydroxy-2'-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which has been widely used as biomarker of oxidative stress, and mental illnesses, including schizophrenia, bipolar disorder and depression. As oxidative DNA damage is caused by reactive oxygen species (ROS), systematic review and meta-analysis were also conducted to analyse the relationship between ROS and these three mental illnesses.
METHODS: Studies from 1964 to 2020 (for oxidative DNA damage) and from 1907 to 2021 (for ROS) in Pubmed and Scopus databases were selected and analysed using Comprehensive Meta-Analysis version 2 respectively. Data were subjected to meta-analysis for examining the effect sizes of the results. Publication bias assessments, heterogeneity assessments and subgroup analyses based on biological specimens, patient status, illness duration and medication history were also conducted.
RESULTS: This meta-analysis revealed that oxidative DNA damage was significantly higher in patients with schizophrenia and bipolar disorder based on random-effects models whereas in depressed patients, the level was not significant. Since heterogeneity was present, results based on random-effects model was preferred. Our results also showed that oxidative DNA damage level was significantly higher in lymphocyte and urine of patients with schizophrenia and bipolar disorder respectively. Besides, larger effect size was observed in inpatients and those with longer illness duration and medication history. Significant higher ROS was also observed in schizophrenic patients but not in depressive patients.
CONCLUSION: The present meta-analysis found that oxidative DNA damage was significantly higher in schizophrenia and bipolar disorder but not in depression. The significant association between deoxyguanosines and mental illnesses suggested the possibility of using 8-OHdG or 8-oxodG as biomarker in measurement of oxidative DNA damage and oxidative stress. Higher ROS level indicated the involvement of oxidative stress in schizophrenia. The information from this study may provide better understanding on pathophysiology of mental illnesses.

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