Association of genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population Bing He a , Junyan Li b , Gang Wang c , Weina Ju d , Yadong Lu a , Yongyong Shi b , Lin He b, ⁎, Nanbert Zhong a,d, ⁎ a Department of Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China b Bio-X Center, Shanghai Jiao Tong University, Shanghai 200030, China c Depression Treatment Center, Anding Hospital, Beijing 100088, China d New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA abstract article info Article history: Received 6 January 2009 Received in revised form 10 April 2009 Accepted 4 May 2009 Available online 7 May 2009 Keywords: Bipolar disorder Case–control study Single nucleotide polymorphism Type II deiodinase Objective: Genetic factors play a critical role in the etiology of bipolar disorder (BPAD). Previous studies suggested an association between thyroid dysfunction and BPAD. We hypothesize that genetic variations in the type II deiodinase (DIO2) gene that possibly alter the bioactivity of thyroid hormones are associated with BPAD. Method: A case–control association study was conducted in a subset of Chinese Han population. Two single nucleotide polymorphisms (SNP), open reading frame a (ORFa)-Gly3Asp (rs12885300) and Thr92Ala (rs225014) with potential functions on the activity of DIO2, were selected. The frequencies of allele, genotype and haplotype of the two SNPs were compared between the BPAD patients and the control group. Results: Statistical significance between the BPAD patients and the control group was observed for the allele (χ 2 = 7.746, P = 0.005, df = 1) and genotype frequencies (χ 2 = 8.158, P = 0.017, df =2) at the locus of ORFa- Gly3Asp, and for the allele (χ 2 = 15.838, P =7.00e-005, df =1) and genotype frequencies (χ 2 = 17.236, P =0.0002, df = 2) at Thr92Ala. Distribution of allele 3Gly and 92Ala were significantly higher in the BPAD patients, with odds ratios of 1.489 [95% confidence interval (CI)=1.124–1.973] and 1.616 [95% CI=1.275– 2.048], respectively. Individuals with two copies of the variant 3Gly or 92Ala were at greater risk of BPAD than individuals with one copy (dose–response manner). Haplotypes ORFa-3Asp-92Ala and ORFa-3Gly- 92Ala indicated higher susceptibility for BPAD with odds ratios of 3.759 (95% CI=2.013–7.020) and 1.292 (95% CI=1.017–1.642), respectively, while ORFa-3Asp-92Thr probably played a protective role with an odds ratio of 0.395 (95% CI = 0.284–0.549). Conclusion: Data generated from this study supported our hypothesis that genetic variations of the DIO2 gene were associated with BPAD and suggested further consideration on the possible involvement of these functionally active variants in the pathophysiology of BPAD. © 2009 Elsevier Inc. All rights reserved. 1. Introduction Bipolar disorder (BPAD) is a major affective disorder marked by severe mood swings (manic or major depressive episodes) with the tendency to remit and recur, affecting around 2.6% of the U.S. population aged 18 and older in a given year (Kessler et al., 2005). The epidemiology of BPAD in Chinese population is still under study. The etiology of BPAD may include genetic, developmental, social, cultural and environmental factors, among which genetic factors have been shown to play an important role through multiple family, twin and adoption studies (Bertelsen et al., 1977; Kendler et al., 1993; Mendlewicz and Rainer, 1977). Although inconsistent results existed, linkage studies have mentioned several loci on chromosome 4 (Adams et al., 1998; Badenhop et al., 2003; Blackwood et al., 1996; Liu et al., 2003), 13q (Detera-Wadleigh et al., 1999; Potash et al., 2003; Stine et al., 1997), chromosome X (Ekholm et al., 2002; Pekkarinen et al., 1995; Zandi et al., 2003), etc. Molecular genetic studies have also identified genes that may be associated with BPAD, such as the catechol-O-methyltransferase (COMT) gene (Lachman et al., 1996; Rotondo et al., 2002), the dopamine transporter (DAT) gene (Green- wood et al., 2001), the 5-hydroxytryptamine transporter (5-HTT) gene (Collier et al., 1996; Rotondo et al., 2002), the monoamine oxidase A (MAOA) gene (Preisig et al., 2000), the brain-derived neurotrophic factor (BDNF) gene (Sklar et al., 2002). Association studies between thyroid function and affective disorders as well as mood instability have a long history, revealing Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 986–990 Abbreviations: 5-HTT, 5-hydroxytryptamine transporter; BDNF, brain-derived neurotrophic factor; BPAD, bipolar disorder; CI, confidence interval; COMT, catechol- O-methyltransferase; DAT, dopamine transporter; DIO2, Type II deiodinase; DNA, deoxyribonucleic acid; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders 4th edition; LD, linkage disequilibrium; MAOA, monoamine oxidase A; ORFa, open reading frame a; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism; SD, standard deviation; SNP, single nucleotide polymorphism; T3, triiodothyronine; T4, thyroxine. ⁎ Corresponding authors. Department of Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Tel./fax: +86 10 82802895. E-mail address: pucmg@pku.edu.cn (N. Zhong). 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.05.003 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp