Molecular Psychiatry (2005) 10, 1097–1103 & 2005 Nature Publishing Group All rights reserved 1359-4184/05 $30.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia W Hennah1, A Tuulio-Henriksson2, T Paunio1,2,3, J Ekelund1,2, T Varilo1,4, T Partonen2, TD Cannon5, JLo¨nnqvist2,3 and L Peltonen1,4,6 1Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland; 2Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland; 3Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland; 4Department of Medical Genetics, University of Helsinki, Helsinki, Finland; 5Departments of Psychology, Psychiatry and Biobehavioral Sciences, UCLA, CA, USA; 6The David Geffen School of Medicine at UCLA, CA, USA We have previously reported evidence of linkage and association between markers on 1q42 and schizophrenia in a study sample of 498 multiply affected Finnish nuclear families, leading to the recent identification of four significantly associated haplotypes that specifically implicate the Translin-Associated Factor X (TRAX) and Disrupted in Schizophrenia 1 and 2 (DISC1 and DISC2) genes in the genetic etiology of schizophrenia. Previously, the DISC genes were found to be disrupted by a balanced translocation (1;11)(q42.1;q14.3) that cosegregated with schizophrenia and related disorders in a large Scottish pedigree. Interestingly, we also reported earlier suggestive linkage between endophenotypic quantitative traits of visual and verbal memory and microsatellite markers in close proximity to TRAX/DISC, on 1q41. Here, we tested if the identified allelic haplotypes of TRAX/DISC would be associated with visual and/or verbal memory function impairments that are known to aggregate with schizophrenia in families. One haplotype of DISC1, HEP3, displayed association with poorer performance on tests assessing short-term visual memory and attention. Analysis of affected and unaffected offspring separately revealed that both samples contribute to the observed association to visual working memory. These results provide genetic support to the view that the DISC1 gene contributes to sensitivity to schizophrenia and associated disturbances and affects short-term visual memory functions. This finding should stimulate studies aiming at the molecular characterization of how the specific alleles of DISC1 affect the visual memory functions and eventually participates in the development of schizophrenia. Molecular Psychiatry (2005) 10, 1097–1103. doi:10.1038/sj.mp.4001731; published online 16 August 2005 Keywords: QTL; Finland; DISC1; schizophrenia Schizophrenia is a severe mental disorder with a consistently observed to be significantly undertrans- strong genetic component,1–3 inherited in a complex mitted to affected individuals. HEP3 also displayed manner. Recently, specific alleles of numerous genes a sex difference in transmission distortion.6 This have been introduced as potential etiological factors association between DISC1 and schizophrenia and of schizophrenia using haplotype association meth- related disorders has recently been replicated.7 How- ods.4,5 On 1q42, haplotypes of a locus containing ever, another study evaluating promoter variants of three such schizophrenia candidate genes, Translin- DISC1 failed to detect association with schizophre- Associated Factor X (TRAX), and Disrupted in nia8 (Figure 1). Schizophrenia 1 and 2 (DISC1 and DISC2), were Initially, linkage analysis had identified 1q42 as a observed to be associated with schizophrenia. Speci- good candidate region for the disorder, when a fically, four different haplotypes (assigned as HEP1– balanced translocation (1;11)(q42.1;q14.3), directly HEP4) were identified in 498 multiply affected disrupting the DISC1 and 2 genes, was observed to Finnish nuclear families with HEP2 and 3 being be linked to schizophrenia and its related disorders in a large Scottish pedigree.9,10 Later, it was shown that a DISC1 intragenic microsatellite marker was linked to Correspondence: Dr L Peltonen, Department of Medical Genetics, schizophrenia in a large Finnish family sample,11 and University of Helsinki, Biomedicum/KTL, MLO, PL 104, 00251, the linkage was replicated with another DISC1 Helsinki, Finland. intragenic marker in an independent Finnish sam- E-mail: [email protected] 12 Received 25 March 2005; revised 6 July 2005; accepted 19 July ple. Observations of linkage to 1q42 to schizophre- 2005; published online 16 August 2005 nia have since been observed in the Taiwanese,13 and DISC1 and quantitative neurocognitive traits W Hennah et al 1098 Figure 1 Schematic diagram of the approximate 600 kb region of 1q42 where the TRAX and DISC genes are located. The diagram shows the exonic structure of the TRAX (gray boxes) and DISC (black boxes) genes, as well as the location of the intragenic exons (white boxes). Above the schematic are marked the linkage findings, and below are marked the association studies, with both positive (black line) and no association (dashed line) findings. The haplotypes from Hodgkinson et al7 referred to here as Hap1 to Hap4 are the haplotypes they refer in their article to as haploblocks. to bipolar disorder in a UK and Icelandic sample14 most telomeric of these markers (ie those immediately (Figure 1). The suggested functions of the TRAX and proximal to TRAX/DISC) displayed the strongest DISC genes also make them highly relevant for the linkage and association to quantitative measures of etiology of psychotic disorders. The DISC1 protein is visuospatial working memory and visual attention.24 implied to play a role in neurite outgrowth, neuronal Also, a family-based, genome-wide scan using a migration, synaptogenesis, and glutamatergic neuro- number of quantitative traits of cognitive functions transmission.15–20 The TRAX protein forms brain- observed some evidence of linkage (lod41.5) to enriched complexes with a protein called Translin, verbal memory functions at the 1q41 locus25 (Figure which is vaguely thought to be involved in the 1). Here, we have tested linked quantitative traits of development and function of the central nervous cognitive functions for association with the consis- system.21 The DISC2 gene has been hypothesized to tently associated haplotypes of 1q42 in Finnish act through its RNA as a regulator of DISC1.9 schizophrenia families. Although multiple findings imply that TRAX/DISC may be involved in schizophrenia, there is currently little data to support any specific etiological model. Materials and methods One approach to address this issue is to use intermediate phenotypes, endophenotypes, of the Study sample clinical diagnosis with a possibly more direct rela- This study used a subsample of families from the tionship to specific molecular pathways. Any mea- original association analysis on 1q42.6 The sample surable quantitative endophenotype of schizophrenia consists of 215 families containing 1437 individuals should represent a heritable state-independent trait, of which 400 are classified as affected according to revealing variations associated with a vulnerability to increasingly inclusive liability classes (LC) with the disorder. Their molecular background is likely to criteria based on the Diagnostic and Statistical be more straightforward, with less genetic hetero- Manual of Mental Disorders, fourth edition (DSM- geneity contributing to the variation in the trait, when IV).26 LC1 constitutes schizophrenia only, LC2 added compared to the diagnostic phenotype of schizophre- those individuals affected with schizoaffective dis- nia. For schizophrenia, the most prominent candidate order, LC3 added individuals with schizophrenia endophenotypes are measures of the structure and spectrum disorder,27 and LC4 added individuals with function of a number of brain systems.22 bipolar disorder or major depressive disorder. From Linkage studies of Finnish schizophrenia samples these 1437 individuals, 746 have undergone extensive have highlighted the 1q41–q42 region as a potential neuropsychological assessment, including 356 off- candidate locus for cognitive endophenotypes. A study spring currently unaffected under LC4 (Table 1). The of Finnish twins used microsatellite markers that 746 assessed individuals have an average age of 50.2 had previously been shown to form a schizophrenia years (SD, 11.6), with 356 female and 390 male linked allelic haplotype spanning 1q32.2–q41.23 The subjects. Molecular Psychiatry DISC1 and quantitative neurocognitive traits W Hennah et al 1099 Phenotypic assessment respectively. Semantic clustering and intrusions were The neuropsychological test battery, from which the logarithmically transformed to normality for all cognitive traits included in this present study were analyses. obtained, has been described elsewhere in detail.28 All tests were well validated, internationally used Laboratory and statistical methods neuropsychological instruments, and include the All single nucleotide polymorphisms (SNPs) had 29 been previously genotyped as part of the original Wechsler Memory Scale-Revised (WMS-R), Califor- 6 nia Verbal Learning Test (CVLT),30 and the Wechsler analysis, in which association was observed for four Adult Intelligence Scale-Revised (WAIS-R).31 The separate haplotypes to LC4, a broad phenotype that tests were administered to the subjects in a fixed predominantly consists of schizophrenia, but also order by experienced