ORIGINAL ARTICLE Association of DISC1 and TSNAX genes and affective disorders in the depression case–control (DeCC) and bipolar affective case–control (BACCS) studies A Schosser 1,8,9 , D Gaysina 1,7,9 , S Cohen-Woods 1 , PC Chow 1 , L Martucci 1 , N Craddock 2 , A Farmer 1 , A Korszun 3 , C Gunasinghe 1 , J Gray 1 , L Jones 4 , F Tozzi 5,6 , J Perry 5,6 , P Muglia 5,6 , MJ Owen 2 , IW Craig 1 and P McGuffin 1 1 MRC SGDP Centre, Institute of Psychiatry, King’s College London, De Crespigny Park, London, UK; 2 Department of Psychological Medicine, Cardiff University, School of Medicine, Heath Park, Cardiff, UK; 3 Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London, UK; 4 Division of Neuroscience, Department of Psychiatry, University of Birmingham, Birmingham, UK; 5 Genetics Division, Drug Discovery, GlaxoSmithKline R&D, Verona, Italy; 6 Genetics Division, Drug Discovery, GlaxoSmithKline R&D, Greenford, Middlesex, UK; 7 Ufa Scientific Center, Institute of Biochemistry and Genetics, RAS, Ufa, Russia and 8 Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria The gene known as Disrupted-in-Schizophrenia-1, DISC1, was originally discovered in a large family, in which it also co-segregated with bipolar affective disorder (BD) and with major depressive disorder (MDD). The TSNAX (Translin-associated factor X) gene, located immediately upstream of DISC1, has also been suggested as a candidate gene in relation to psychiatric illness, as one transcript resulting from intergenic splicing encodes a novel TSNAX–DISC1 fusion protein. We explored the TSNAX–DISC1 gene region for an association with BD and MDD in a sample of 1984 patients (1469 MDD, 515 BD) and 1376 ethnically matched controls. Eight single nucleotide polymorphisms (SNPs) within the TSNAX–DISC1 region (rs766288, rs3738401, rs2492367, rs6675281, rs12133766, rs1000731, rs7546310 and rs821597) were investigated using the SNPlex Genotyping System. We found a significant allelic and genotypic association of the TSNAX–DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD. Therefore, our results suggest an association between the TSNAX–DISC1 region and both forms of affective disorders, and support the hypothesis that a portion of the genotypic overlap between schizophrenia and affective disorders is attributable to this gene. Molecular Psychiatry (2010) 15, 844–849; doi:10.1038/mp.2009.21; published online 3 March 2009 Keywords: bipolar disorder; depression; association; psychosis Introduction Recent twin studies suggest correlations between the liabilities to unipolar or major depressive dis- order (MDD) and to bipolar disorder (BD), 1 as well as between BD and schizophrenia (SZ). 2 Association studies also provide evidence for overlap in genetic susceptibility across the traditional classification categories. 3 The Disrupted-in-Schizophrenia-1 (DISC1) gene was initially identified at the breakpoint of a balanced translocation (1,11)(q42.1;q14.3), which segregated with major mental illnesses (SZ, schizo- affective disorder, BD, unipolar affective disorder and adolescent conduct disorder) in a large Scottish family. 4 Thus, DISC1 is a putative susceptibility gene for psychoses, suchas SZ and BP, as well as for MDD. A number of key central nervous system proteins, thought to be highly relevant to the development of mental illness, have also been identified as inter- acting partners (for review, see Chubb et al. 5 ), and several DISC1 interactors have been defined as independent genetic susceptibility factors for major mental illness. The translin-associated factor X (TSNAX) gene is located immediately upstream of DISC1, and inter- genic splicing (splicing together of exons from separate genes) between the DISC1 and the gene encoding TSNAX was shown by Millar et al. 6 One transcript resulting from intergenic splicing encodes a novel TSNAX–DISC1 fusion protein, and TSNAX has been suggested to be considered as a candidate gene in relation to psychiatric illness as well. Evidence for an association between BD and SZ and the Received 1 December 2008; accepted 14 January 2009; published online 3 March 2009 Correspondence: Dr A Schosser, MRC SGDP Centre, Institute of Psychiatry, King’s College London, Box P080, De Crespigny Park, London SE5 8AF, UK. E-mail: alexandra.schosser@iop.kcl.ac.uk 9 These two authors contributed equally to this work. Molecular Psychiatry (2010) 15, 844–849 & 2010 Macmillan Publishers Limited All rights reserved 1359-4184/10 www.nature.com/mp