disc1 pathway expression in mouse and man

variation in ErbB4 (Haplotype rs7598440, rs707284, rs839523).PI3KCD expression phenotypes were also examined in the humanbrain in the disease. Tag SNPswere selected in PI3KCD alongwith anycoding variations in the NCBI database. 20 SNPs were genotyped inthree independent clinical samples, two family based and one case-control. Main effects analyses of single SNPs and haplotypes wereconducted using unconditional logistic regression in the case-controlsamples and using the family-based association test (FBAT) infamilies. Epistasis between DNA variants in ErbB4 and PI3KCD weretested in both the case-control and family samples using uncondi-tional and conditional logistic regression. Results: Disease state andthe ErbB4 risk haplotype were associated with differential expres-sion of a PI3KCD/p55gamma complex in lymphocytes, downstreamof changes in ErbB4 splice gene expression and upstream of alteredNRG1-mediated intracellular PIP3 signaling and NRG1-induced cellmigration. At the clinical genetic level, we report distortedtransmission of SNP alleles in PI3KCD in two independent family-based samples and epistasis between ErbB4 and PI3KCD.Discussion: Our results provide direct experimental and geneticevidence that complex diseases such as schizophrenia are emergentproperties of interacting molecular networks modified by geneticloci. Variation in expression of the ErbB4 gene in relation to risk forschizophrenia has downstream functional consequences for thePI3K pathway at both the molecular and cellular phenotype level. Asystems biology approach to elucidating the architecture ofaberrant signaling networks in schizophrenia in relation to geneticrisk has significant value for the identification of novel risk genesand for the development of new targeted therapeutics.

doi:10.1016/j.schres.2010.02.009

DISC1 PATHWAY EXPRESSION IN MOUSE AND MAN

David PorteousUniversity of Edinburgh, Edinburgh, UK

Background: DISC1 is nowwell established as a genetic risk factor fora range of major mental illnesses, mediated through the role of DISC1as a hub protein which interacts with multiple binding partners toregulate neurodevelopment and neurosignalling pathways. MethodsHere, we describe the outcome of transcriptional profiling studies inthe following experimental contexts: 1. Comparative analysis of fetaland adult brain expressionprofiles in theQ31L and L100PDisc1mouselines and the effect of behaviour modifying drug treatment in theL100P Disc1 line. 2. Transcriptional profiles of human lymphoblastoidcell lines with and without the t(1;11) translocation which disruptsDISC1. 3. The effect of common SNP variants of DISC1, PDE4 and NDE1on transcriptional profiles of human lymphoblastoid cell lines. Results1. GO Tree analysis of differentially expressed genes found over-representation of cell-cell signalling, transmission of nerve impulses,synaptic transmission, neurotransmitter secretion, vesicle dockingduringexocitosis andperipheralnervous systemdevelopment, overlapwith schizophrenia-associated CNV loci and independent DISC1pathwayanalyses. 2. The effect of the t(1;11) is to dysregulatemultiplesignalling pathways. Genes showing significantly altered expressioninclude candidate SZ/Autism genes and synaptic genes. 3. Disc1pathway variants selectively modulate the expression of cytoskeletal,synaptogenetic, signalling and sensory perception genes. The Disc1regulome is enriched for proteins that are current targets forpsychiatric drug development. Conclusions In addition to the directeffects of DISC1 interaction with protein partners, the DISC1interactome, common variants and rare mutations in DISC1 directlyand indirectly affect global patterns of expression. These DISC1 relatedtranscriptional profiles may serve as useful central and peripheralbiomarkers of disease and response to treatment. Sarah Brown1,

William Hennah1,2, Christoph Grunewald1, Xu Tang1, L. MiguelCamargo3, Steven Clapcote1,4, Kirsty Millar1 Pippa Thomson1, KathyEvans1 & David Porteous1 1Medical Genetics Section, University ofEdinburgh Molecular Medicine Centre and Institute of Genetics andMolecular Medicine, Edinburgh EH4 2XU, UK. 2Institute for MolecularMedicine Finland, National Institute for Health and Welfare, Biome-dicum Helsinki, FI-00251, Finland 3Merck Research LaboratoriesBoston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. 4Instituteof Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT,UK.

doi:10.1016/j.schres.2010.02.010

Special SessionPSYCHOSOCIAL SESSION - AN UPDATE ON PSYCHOSOCIALTREATMENT OF SCHIZOPHRENIAChairperson: Kim MueserSunday, 11 April, 2010 - 1:30 pm - 3:30 pm

Overall Abstract: Significant advances have been made over thepast several years in the psychosocial treatment of schizophrenia.This symposium brings together international experts who willprovide an update on recent developments in cognitive behavioraltherapy for psychosis, family psychoeducation, assertive commu-nity treatment, vocational rehabilitation, cognitive remediation, andsocial skills training. In addition, the symposium will describe tworecently funded projects by NIMH that are developing andvalidating first episode psychosis programs designed to beimplemented in the U.S. healthcare system.

doi:10.1016/j.schres.2010.02.011

FIRST EPISODE PSYCHOSIS AND ASSERTIVE COMMUNITYTREATMENT

Lisa DixonUniversity of Maryland School of Medicine, Baltimore, MD, USA

Avariety of team-based approaches have proven to be effective forthe care of persons with schizophrenia. Assertive CommunityTreatment (ACT) is an established evidence-based model. The mostrecent Schizophrenia Patient Outcomes Research Team (PORT) reviewrecommended ACT on the basis that it reduces hospitalization andhomelessness. When compared to standard community care, Co-chrane reviews have found that those receiving ACT were more likelyto remain in contact with services, were less likely to be admitted tohospital. and spent less time in hospital. Those receiving ACT also hadmore favorable accommodation status, employment and patientsatisfaction. Recent attempts to focus on substance abuse and assistingforensic populations have yielded mixed results suggesting that morework is necessary to understand how to extend and focus ACT'seffectiveness. Multi-element team-based models analogous to ACThave also been tested in the care of individuals with recent onset ofschizophrenia. Studies conducted in Europe and Australia havesuggested a range of possible benefits of team basedmodels includingreduced symptoms, substance abuse, treatment retention, and socialand occupational functioning. One of the US NIMH-funded RecoveryAfter an Initial Schizophrenia Episode (RAISE) initiatives developed bythe Research Foundation for Mental Health team (Lieberman, PI,Dixon, Co-PI) will employ a team-based approach that builds onprinciples of ACT, Critical Time Intervention(CTI)models, andprevious

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