Neuroscience Letters 367 (2004) 232–234 X-box binding protein 1 (XBP1)C-116G polymorphisms in bipolar disorders and age of onset Sheue-Jane Hou a , Feng-Chang Yen a , Chih-Ya Cheng b,c , Shih-Jen Tsai b,c , Chen-Jee Hong b,c,∗ a Division of Psychiatry, Cheng-Hsin Rehabilitation and Medical Center, Taipei, Taiwan, ROC b Department of Psychiatry, Taipei Veterans General Hospital, No. 201 Shih-Pai Road, Sec. 2, 11217 Taipei, Taiwan, ROC c School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC Received 17 March 2004; received in revised form 25 May 2004; accepted 4 June 2004 Abstract X-box binding protein 1 (XBP1), a critical gene in the endoplasmic reticulum stress response, is located on chromosome 22q12, which has been linked with bipolar disorders in several studies. Recently, associations have been reported between a polymorphism (-116C → G) in the promoter region of XBP1, and bipolar disorders in both case-control study and family-based association study, however, this finding is not yet confirmed by other research using independent sample populations. To replicate this finding and determine the association between onset age of bipolar disorders and the XBP1 C-116G polymorphism, we investigated the prevalence of this polymorphism in a Chinese population (153 bipolar disorder patients and 174 controls). We were unable, however, to demonstrate a significant association between the C-116G polymorphism and bipolar disorders (P = 0.674 for genotype and P = 0.436 for allele frequency) or age at onset (P = 0.563). Further, no association was demonstrated between this polymorphism and family history in bipolar disorder patients. These negative findings suggest that the XBP1 C-116G polymorphism does not play a major role in the pathogenesis of bipolar disorders in Chinese populations. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: X-box binding protein 1; Association study; Bipolar disorders; Polymorphism; Age of onset The pathogenesis underlying bipolar disorders remains unknown, however, analysis of the genetic data strongly indicates a significant genetic involvement in their develop- ment. For example, first-degree relatives of bipolar disorder probands are 5–10 times more likely than the first-degree relatives of controls to have bipolar disorders (for review see [3]). In addition, twin studies of bipolar disorders have shown an increased risk for monozygotic twins compared with dizygotic analogs of a proband with bipolar disorders [1,12]. In the last decade, the availability of modern genetic techniques has led to many studies reporting various associ- ations between specific genes or gene markers and bipolar disorders, however, these positive findings have not been consistently replicated. Recently, Kakiuchi et al. [7] reported that X-box binding protein 1 (XBP1), a pivotal gene in the endoplasmic reticu- ∗ Corresponding author. Tel.: +886 2 2875 7027x268; fax: +886 2 2872 5643. E-mail address: cjhong@vghtpe.gov.tw (C.-J. Hong). lum (ER) stress response, contributed to the genetic risk for bipolar disorders in a Japanese sample of bipolar disorder patients and normal controls. Initially, these workers used DNA microarray analysis of lymphoblastoid cells derived from two pairs of monozygotic twins discordant for bipo- lar disorders to determine down-regulated expression of two genes (XBP1 and heat shock 70 kDa protein 5) related to ER stress response in affected siblings, with this finding fur- ther confirmed by RT-PCR. Additionally, a polymorphism (-116C → G) in the promoter region of XBP1, affecting its putative binding site, was associated with bipolar disorders. Further, the -116G allele, which has lower XBP1-dependent transcription activity than the -116C allele, was markedly more common in this Japanese population of bipolar disor- der patients than normal controls [7], and over-transmitted to affected offspring in trio samples sourced from the Bipolar Disorder Genetics Initiative of the National Institute of Men- tal Health [5]. The proposed association between the XPB1 gene and bipolar disorders is further supported by the finding that sodium valproate, an anticonvulsant and mood stabilizer, 0304-3940/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.06.012