Association of functional polymorphisms in 3′-untranslated regions of COMT, DISC1, and DTNBP1 with schizophrenia: a meta-analysis Zahra I. Mohamed a , Shiau F. Tee b and Pek Y. Tang a 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. Psychiatr Genet 28:110–119 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Psychiatric Genetics 2018, 28:110–119 Keywords: COMT, DISC1, DTNBP1, meta-analysis, schizophrenia Departments of a Mechatronics and Biomedical Engineering and b Chemical Engineering, Lee Kong Chian Faculty of Engineering and Science, Universiti Tunku Abdul Rahman, Kajang, Malaysia Correspondence to Pek Y. Tang, PhD, Department of Mechatronics and Biomedical Engineering, Lee Kong Chian Faculty of Engineering and Science, Universiti Tunku Abdul Rahman, Bandar Sungai Long, Cheras 43000 Kajang, Malaysia Tel: + 60 390 860 288; fax: + 60 390 198 868; e-mail: tangpy@utar.edu.my Received 24 January 2018 Revised 14 August 2018 Accepted 5 September 2018 Introduction Schizophrenia is a serious mental disorder that affects almost 1% of the general world population. The symp- toms of this disorder fall into three categories, which are positive symptoms, negative symptoms as well as cogni- tive symptoms (Patel et al., 2014). Positive symptoms include hallucination, delusion as well as thought dis- order, whereas patients with negative symptoms experi- ence commotion of normal emotion. Meanwhile, poor memory function and other aspects of thinking such as poor executive functioning and trouble in focusing are prominent in patients with cognitive symptoms. The heritability of schizophrenia has reached as high as ~ 80%. The contemporary working hypothesis regarding the etiology of this disorder mentions that multiple genetic and nongenetic risk factors of small to large effects play important roles in the etiology of schizophrenia through an interaction with each other (Giusti-Rodríguez and Sullivan, 2013; Clifton et al., 2017). The expression of numerous genes was associated with subtle abnormalities in multiple brain regions in patients with schizophrenia. An expression study found 332 upregulated and 361 downregulated genes in the dorso- lateral prefrontal cortex of patients with schizophrenia (Fromer et al., 2016). In schizophrenia, changes in gene expression may be caused by several factors such as sequence variants in regulatory regions of genomic DNA, epigenetic modification, as well as environmental con- found (e.g. medications). Cis-acting and trans-acting genetic influences can be observed in altered expression result from DNA variation (Bray, 2008). Cis-acting reg- ulatory variants can be found in the promoters, exonic and intronic regions, as well as control elements (Levine and Tjian, 2003). Three-prime untranslated region (3′-UTR) in the asso- ciated genes has important roles in the development of schizophrenia, as primarily 3′-UTRs are responsible in the post-transcriptional regulation of gene expression, including transporting mRNAs out of the nucleus, translation efficiency, gene stability, and subcellular localization. The 3′-UTR has several regulatory func- tions. In this region, there are regulatory sequences such as polyadenylation signals and binding sites for micro- RNA (miRNA). The long sequence of 3′-UTR is 110 Original article 0955-8829 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/YPG.0000000000000210 Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.