Association study of TPH2 polymorphisms and bipolar disorder in the Han Chinese population Shiqing Chen a , Xiaoye Huang a , Tao Yu a , Xin Li a , Yanfei Cao a , Xingwang Li a , Fei Xu a , Fengping Yang a , Forrest Fabian Jesse a , Mingqing Xu a , Weidong Li a , Lin He a,b,c, ⁎, Guang He a, ⁎⁎ a Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China b Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China c Institute for Nutritional Sciences, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China abstract article info Article history: Received 4 April 2014 Received in revised form 26 July 2014 Accepted 16 August 2014 Available online 21 August 2014 Keywords: Association Bipolar disorder Case–control study Chinese Han population TPH2 Objective: Bipolar disorder (BPD) is a serious and common mental disorder with high heritability. The serotoner- gic system is known to be implicated in the etiology of the disorder. Tryptophan hydroxylase isoform-2 (TPH2), which controls the synthesis of serotonin in the brain, has been suggested as a candidate gene for BDP. The aim of this study was to examine the association between the polymorphisms in TPH2 and BPD. Methods: We conducted a case–control study by genotyping six SNPs (rs10784941, rs1386494, rs2171363, rs4760816, rs1386486, and rs1872824) in 506 bipolar patients and 507 controls of Chinese Han origin. Results: rs10784941 was not in the Hardy–Weinberg equilibrium and therefore excluded from further analysis. rs1386486 and rs1872824 showed statistically significant differences between cases and controls in genotype frequencies (rs1386486: p = 0.043351; rs1872824: p = 0.016563), but no association in allele frequencies. Strong LD was found among rs1386494, rs2171363 and rs4760816, but no positive association with BPD was found for haplotypes. Conclusion: Our results indicate that in the Han Chinese population TPH2 may be a potential susceptibility gene for bipolar disorder. Further studies are needed to validate this association. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Bipolar disorder (BPD) is a common and severe mood disorder char- acterized by mania or hypomania and depression (Craddock and Sklar, 2013). The disability caused by BPD and the high incidence of relapse re- sult in huge personal and social burdens. Recent estimation of the life- time prevalence of bipolar disorder was made at 2.4% (Merikangas et al., 2011). BPD has a strong genetic basis with high heritability (Althoff et al., 2005; Smoller and Finn, 2003), and many candidate regions and genes have been reported (Barnett and Smoller, 2009; Serretti and Mandelli, 2008). Several association and functional studies have found that the serotonergic system is involved in the pathogenesis of BPD, and that tryptophan hydroxylase isoform-2 (TPH2) plays a key role in the serotonergic system. Serotonin (5-HT) is an important neurotransmitter implicated in various physiological processes, such as cell proliferation, mobility, dif- ferentiation, organ development, neuronal migration and synaptogene- sis (Gaspar et al., 2003). It has been suggested that 5-HT is involved in certain pathological functions in the central nervous system (Lucki, 1998; Meltzer et al., 1998). Previous studies have shown that the ex- pression of 5-HT is lower in the brains of BPD patients (Sobczak et al., 2002). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin (5HT), and has two isoforms, TPH1 and TPH2. TPH1 is mainly expressed in the peripheral nervous system, whereas TPH2, located on chromosome 12q21, is preferentially expressed in the brain to control 5-HT synthesis in the central nervous system (Walther et al., 2003; Zhang et al., 2004; Zill et al., 2004). Some studies have indicated that TPH2 is associated with BPD (Campos et al., 2011; Cichon et al., 2008; De Luca et al., 2005; Harvey et al., 2007; Lin et al., 2007; Roche and McKeon, 2009; Van Den Bogaert et al., 2006; Xiang et al.,2014), although the opposite results have also been reported (Campos et al., 2010; Choi et al., 2010). This study was designed to examine the association between TPH2 polymorphisms and BPD. We identified six single nucleotide Progress in Neuro-Psychopharmacology & Biological Psychiatry 56 (2015) 97–100 Abbreviations: BPD, bipolar disorder; DR, dorsal raphe nucleus; DSM-IV, Diagnostic and Statistical Manual for Mental Disorders, 4th Edition; LD, linkage disequilibrium; PD, panic disorder; SNP, single nucleotide polymorphism; TPH, tryptophan hydroxylase; TPH2, tryptophan hydroxylase isoform-2. ⁎ Correspondence to: L. He, Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China. Tel./fax: +86 21 62822491. ⁎⁎ Correspondence to: G. He, Bio-X Institutes, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, China. Tel./fax: +86 21 62822491. E-mail addresses: helinhelin3@gmail.com (L. He), heguang@sjtu.edu.cn (G. He). http://dx.doi.org/10.1016/j.pnpbp.2014.08.008 0278-5846/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry