Genetic association of LMAN2L gene in schizophrenia and bipolar disorder and its interaction with ANK3 gene polymorphism Chor Hong Lim a, ⁎, Shamsul Mohd Zain a , Gavin P. Reynolds b , Mohd Aizat Zain a , Siti Norsyuhada Roffeei a , Nor Zuraida Zainal c , Sharmilla Kanagasundram c , Zahurin Mohamed a a The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia b Biomedical Research Centre, Sheffield Hallam University, City Campus, Howard Street, Sheffield S11WB, UK c Department of Psychological Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia abstract article info Article history: Received 25 March 2014 Received in revised form 19 May 2014 Accepted 29 May 2014 Available online 8 June 2014 Keywords: ANK3 Bipolar disorder LMAN2L Polymorphism Schizophrenia Recent studies have shown that bipolar disorder (BPD) and schizophrenia (SZ) share some common genetic risk factors. This study aimed to examine the association between candidate single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) and risk of BPD and SZ. A total of 715 patients (244 BPD and 471 SZ) and 593 controls were genotyped using the Sequenom MassARRAY platform. We showed a positive association between LMAN2L (rs6746896) and risk of both BPD and SZ in a pooled population (P-value = 0.001 and 0.009, respectively). Following stratification by ethnicity, variants of the ANK3 gene (rs1938516 and rs10994336) were found to be associated with BPD in Malays (P-value = 0.001 and 0.006, respectively). Further- more, an association exists between another variant of LMAN2L (rs2271893) and SZ in the Malay and Indian eth- nic groups (P-value = 0.003 and 0.002, respectively). Gene–gene interaction analysis revealed a significant interaction between the ANK3 and LMAN2L genes (empirical P = 0.0107). Significant differences were shown be- tween patients and controls for two haplotype frequencies of LMAN2L: GA (P = 0.015 and P = 0.010, for BPD and SZ, respectively) and GG (P = 0.013 for BPD). Our study showed a significant association between LMAN2L and risk of both BPD and SZ. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Bipolar disorder (BPD) is a severe mental disease with profound so- cial and economic impacts. BPD accounted for 7% of disability-adjusted life years worldwide, as indicated by the Global Burden of Diseases 2010 report (Whiteford et al., 2013). The etiology of BPD has yet to be fully understood, although one hypothesis that is gaining much support is the involvement of ion channelopathy (Ferreira et al., 2008). Genome- wide association studies (GWAS) have identified susceptibility genes associated with BPD, a few of which are in a class of genes related to the structure and regulation of ion channel (Ferreira et al., 2008; Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011). The notion of ion channel involvement is further supported by findings of increased intracellular calcium in the lymphocytes of BPD patients (Brotman et al., 1986; Goodnick, 2000) and the effectiveness of calcium channel blockers in the treatment of BPD (Hough et al., 1999). These findings add weight to the evidence for cellular calcium imbalance and calcium ion channelopathy in the etiology of BPD. In considering a possible association of BPD with genetic variants, their interplay with schizophrenia (SZ) cannot be overlooked. Although the two disorders may present distinct symptoms, growing evidence has shown that they share some common genetic variations (Berrettini et al., 2000; Lichtenstein et al., 2009; Maier et al., 2005, 2006). Confirmation of results from GWAS in a well-characterized pop- ulation is an important approach to identify the susceptibility loci for BPD and SZ. In this study, we aimed to examine the association between BPD and several single nucleotide polymorphisms (SNPs) from candi- date genes identified in the GWAS. Among these genes are those in- volved in ion channel transport (BTF3L1/KCTD12 and ANK3) and endoplasmic reticulum (ER) transport (LMAN2L). Considering the possible genetic overlap between BPD and SZ, we set out to examine the association between variants within these genes and these disorders. We hypothesized the root genetic cause of BPD and SZ by highlighting genetic variants that overlap in both disor- ders, as well as the genetic variants that are distinctly different between the two conditions. The BPD and SZ patients in our study were of three Progress in Neuro-Psychopharmacology & Biological Psychiatry 54 (2014) 157–162 Abbreviations: BPD, bipolar disorder; SZ, schizophrenia; SNP, single nucleotide poly- morphism; GWAS, genome-wide association studies; ANK3, ankyrin-G protein; KCTD12, potassium channel tetramerization domain containing 12; LMAN2L, lectin, mannose- binding 2-like; UMMC, University Malaya Medical Centre; LD, linkage disequilibrium; GMDR, Generalized Multifactor Dimensionality Reduction; ER, endoplasmic reticulum; HWE, Hardy–Weinberg equilibrium; OR, odds ratio; CI, confidence interval. ⁎ Corresponding author at: The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Tel.: +60 3 7967 4702/4703; fax: +60 3 7967 4791. E-mail address: limchorhong@yahoo.com (C.H. Lim). http://dx.doi.org/10.1016/j.pnpbp.2014.05.017 0278-5846/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp