Association study of 5-HT2A genes with schizophrenia in the Malaysian population: A Multiethnic Meta- analysis Study Shiau Foon Tee* 1, Tze Jen Chow 1, Pek Yee Tang 1, 1 Faculty of Engineering and Science, Universiti Tunku Abdul Rahman, Jalan Genting Kelang, Setapak, Kuala Lumpur, Malaysia. Tel: , Fax: *

Introduction Serotonin (5-hydroxytryptamine, 5-HT) is a key neurotransmitter in the pathogenesis of schizophrenia due to its role in many physiological processes (Zhang et al, 2004). A functional promoter variant of the 5-HT2A receptor gene might differentially alter transcription, thereby affecting the number of receptors. The –1438 G/A SNP was found to be associated with schizophrenia (Gu et al, 2013), while the 5-HT2A 102T/C is another biologically functional SNP that has been investigated in schizophrenia (Yildiz et al, 2013).

Objectives To investigate the genotype distribution of 5-HT2A T102C and -A1438G polymorphisms. To further reconcile the conflicting association between variants in 5-HT2A and schizophrenia, meta-analysis was performed by combining our findings and the results all relevant association studies.

Materials and Methods Consent was obtained from every individual for blood withdrawal. Patients = 417, Healthy controls = 429 All the patients are from Hospital Bahagia Ulu Kinta and fulfilled the criteria of Mini International Neuropsychiatric Interview (M.I.N.I). Peripheral blood samples were collected from all subjects. Genomic DNA has been extracted. PCR-RFLP was performed to genotype the COMT Val158Met and 5-HTR2A T102C polymorphisms. Allelic and genotype frequency differences between patients and controls were analysed using the chi-square (χ 2 ) test of the Statistical Package for the Social Sciences (SPSS), version By pooling our data and previous independent studies, meta-analysis was conducted using Comprehensive Meta Analysis (Version 2.0, BIOSTAT, Englewood NJ, USA).

Results SNPAllele (%)Genotype (%) -A1438G (rs6311)AGAAAGGG Patients428 (58.5)304 (41.5)127 (34.7)174 (47.5)65 (17.8) Controls523 (71.4)209 (28.6)214 (58.5)95 (26.0)57 (15.6) χ 2 (df)3.483 (1)7.158 (2) P-value * OR (95%CI)0.574 (0.319 – 1.031) T102C (rs6313) Patients530 (72.4)202 (27.6)195 (53.3)140 (38.2)31 (8.5) Controls512 (69.9)220 (30.1)188 (51.4)136 (37.2)42 (11.5) χ 2 (df)0.097 (1)0.480 P-value OR (95%CI)1.102 (0.598 – 2.031) Table 1: Allelic and genotypic frequencies of the two SNPs in 5-HT2A for the pooled Malaysian patients and controls

Figure 1: Egger’s funnel plots of publication bias analysis for studies A1438G in Asians (a1) and Caucasians (a2) and T102C in Asians (b1) and Caucasians (b2) with schizophrenia. a1 a2 b1 b2

Discussion Discordant findings and failures to replicate candidate genes when studying complex genetic diseases have been attributed to several causes, mainly sample size, population stratification effect, disease heterogeneity, and symptomatology (Thomas and Witte, 2002). There is a possibility of genetic heterogeneity among our samples which leads to false negative. Secondly, the discrepancy may be due to disease heterogeneity of the patient samples (Ross, 2014). Joober et al. (1999) found significant differences between the genotype frequencies of male neuroleptic-nonresponder patient with schizophrenia and controls. Arranz et al. (1995) observed that homozygosity for the 102C allele was more frequent among patients who did not respond to clozapine than in those who responded.

Conclusion It was suggest that -1438G/A may significantly involve in the pathogenesis of schizophrenia. However, the functional implication of this polymorphism in schizophrenia remains to be elucidated. Acknowledgements The work was supported by Ministry of Higher Education, Malaysia, [project numbers: FRGS/2/2010/SKK/UTAR/03/4 and FRGS/1/10/ST/UTAR/03/5]. The authors thank the mental health professionals of Ulu Kinta Psychiatric Hospital and all volunteers.