Genetics and Translational Psychiatry

1. Genetics and Translational Psychiatry Mike Owen Dept Psychological Medicine School of Medicine.

2. IRG in Neurosciences and Mental Health MRC Co-operative Group in Genetics of Psychiatric and Neurodegenerative Disorders Psychological Medicine: Profs Derek Blake, Nick Craddock, Peter Holmans, Mike O’Donovan,Mike Owen, Mary Phillips, Anita Thapar, Julie Williams, Lawrence Wilkinson. Readers Paul Buckland, Lesley Jones S/Ls Anthony Isles, Ian Jones, George Kirov, Marianne van den Bree, Nigel Williams, Stan Zammit. RCUK Fellows Will Davies,Valentina Moskvina. Neurology: Anne Rosser, S/L Huw Morris. Psychology:Profs Dale Hay, Simon Killcross. Reader Gordon Harold. nCL Trevor Humby Biosciences:Prof Steve Dunnett.

3. Genetic Epidemiology Genomics Functional Studies Epidemiology Mission Clinical and Translational Using genetics and genomics to inform our understanding of the aetiology, pathogenesis, classification and treatment of the major psychiatric and neurodegenerative disorders.

4. Why look for genes for mental disorders? • These are important diseases that place great burdens on the individual and society • Genes play a substantial part in determining susceptibility • We generally lack of other clues. • The power of genomics to find genes for common diseases. • Lack of understanding of aetiology and pathogenesis. • Genomic approaches do not require existing clues about causes or disease processes. • Identifying genes will help us understand fundamental disease processes, and develop novel treatments and new approaches to diagnosis.

5. Why look for genes for mental disorders? • These are important diseases that place great burdens on the individual and society • Genes play a substantial part in determining susceptibility • We generally lack of other clues. • The power of genomics to find genes for common diseases. • Lack of understanding of aetiology and pathogenesis. • Genomic approaches do not require existing clues about causes or disease processes. • Identifying genes will help us understand fundamental disease processes, and develop novel treatments and new approaches to diagnosis.

6. Major Themes • Psychosis and Major Affective Disorders • Blake, Craddock, Jones I, Killcross, Kirov, O’Donovan, Owen, Wilkinson, Williams N, Zammit. • Neurodegenerative Disorders • Blake, Dunnett, Jones, L, Morris, O’Donovan, Owen, Rosser, Williams, J. • Developmental Disorders • Craddock, Harold, Hay, Jones I, Killcross, Kirov, O’Donovan, Owen, Thapar, van den Bree, Williams, J, Williams N. • Mouse Behavioural Genetics/Epigenetics • Davies, Humby, Isles, Killcross, Wilkinson. • Bioinformatics and Biostatistics Unit • Hamshere, Holmans, Moskvina,Nikolov, Seguardo, Singh

7. Schizophrenia positional genetics (MRC Programme). Schizophrenia myelination genes (NIMH Conte Center). Mood-Psychosis Spectrum (Wellcome Trust Programme). Dysbindin in schizophrenia (WT project). Pharmacogenetics of depression (MRC, EU). Endophenotypes in schizophrenia (MRC CRTF). G*E of PLIKS (DoH Clinician Scientist Award). Large linkage scans for SZ and BP which resulted in the generation of genome-wide significant linkage. Identification of OLIG2, CNP and PTPRZ1 as SZ risk genes implicating altered oligodendrocyte function. Identified and characterized dysbindin, first demonstration of how disease-associated variants in dysbindin alter gene function. Empirical and theoretical exploration of SZ-BP boundary. Identification of GNB1L and TBX1 as risk genes for SZ on 22q11. CGH study of SZ- NRXN1 and APBA2. GWA of BP (WTCCC). GWA of SZ Identified important relationships between risk of psychosis and cannabis smoking, cigarette smoking, and IQ. Suggestion of link between genetic findings in schizophrenia and glutamatergic neurotransmission. Psychosis and Major Affective Disorders

8. Alzheimer’s disease positional genetics (MRC Programme, WT project, ART Centre). Alzheimer’s disease proteomics (AS) Huntington’s disease transplantation, comparative molecular pathology (MRC Programme, MRC, HighQ, EU). Parkinson’s Disease (PDS) PSP (PSPA) The molecular neurobiology of muscular dystrophy. (Wellcome Trust Senior Fellowship to Blake) Identified linkage to chromosome 10 Identified 4 novel putative Alzheimer’s disease genes. MRC AD Genetics Resource. GWA study of AD by pooled genotyping. Full GWA funded by WT Used a synthesis of transgenic mouse technology, behaviour analysis, global gene expression, and drug exposure to identify a drug regimen with the potential to improve cognition in Huntington’s disease. Published first UK safety and feasibility study for human neural transplantation in Huntington's disease. Discovered a new rodent model for preclinical testing of donor cells for neural transplantation. First transcriptomic characterisation of HD brain and comparison with multiple mouse models Fukutin-related protein (FKRP) mutations cause structural brain abnormalities and cognitive impairment. Neurodegenerative Disorders

9. Dyslexia positional genetics (EU FP6). ADHD positional genetics (WT Programme). Childhood depression-risk detection (Sir Jules Thorn Award for Biomedical Research). Pre-natal environmental influences on behaviour (WT). Implicated KIAA0319 as a susceptibility gene for dyslexia (cited by Science as one of the breakthrough findings of 2005) Identified specific gene-environment interaction increasing risk for ADHD. Established co-morbid antisocial behaviour as a clinically important sub-phenotype of ADHD. Identified COMT as risk locus for anti-social behaviour in ADHD. Developmental Disorders

10. Genomic imprinting effects on behaviour X-linked behaviours/sexual dimorphisms Gene variants influencing impulsive behaviours Dementia models (Psychosis models) Cardiff University LINK Chair 2006. MRC, Wellcome Trust, Health Foundation/Beebe Trust, ART, GSK plc Discovered X-linked genomic imprinting effects on cognition. New molecular targets on the X chromosome influencing fear. Linkage of Sts dosage to attentional deficits in ADHD. Heritable effects on impulsive responding and hyperactivity. Demonstration of molecular links between APP and tau in AD. Mouse Behavioural Genetics/Epigenetics

11. Established 2003, funded by HEFCW - RCDF (£1.48M over 3 years). Innovative Biostatistics and Bioinformatics research. Support analytic and data management needs of MRC Co-op. Training in Biostatistics and Bioinformatics. Established for 4 years and has 6 core staff (2 supported by school and 2 by MRC Co-op) and 6 affiliated. Contributed to 186 papers submissions (159 accepted) and 26 successful grants applications resulting in £9.5M research funding. It has established a series of Post-Graduate Masters/Diploma Courses in Biostatistics and Bioinformatics attended by graduates and PhD students. Developing distance learning approaches.

12. Future Strategy

13. Clinical and Translational Genetic Epidemiology Genomics Functional Studies Epidemiology Future Strategy: Genetic Epidemiology. • GE interplay • Developmental psychopathology, substance abuse/addiction • Role of prenatal environment • Collaboration with PSYCHOL • Development of resources • CASTANET, ALSPAC

14. Clinical and Translational Genetic Epidemiology Genomics Functional Studies Epidemiology Future Strategy: Genomics. • Major genomics programmes • SZ, BP, AD, ADHD, Dyslexia, Puerperal psychosis • WGA, CNV • WTCCC2 • Developing foci • Pharmacogenetics, UPD, PD, Substance abuse. • Supported by strong and innovative clinical, laboratory, data management and statistical infrastructure. • Links with WTSC and Broad.

15. Clinical and Translational Genetic Epidemiology Genomics Functional Studies Epidemiology Translating Genetic Findings. • Gene function, Heterogeneity and co-morbidity • Clinical samples • Endophenotypes • Gene function, pathophysiology • Cell biology • Human tissue • Animal Models • Population effects, GG, GE etc. • Epidemiological samples • Longitudinal studies

16. Clinical and Translational Genetic Epidemiology Genomics Functional Studies Epidemiology Translating Genetic Findings. • Relating genes to functional systems and psychopathology • Impact on classification and nosology • Cognitive and Imaging endophenotypes • gene function • experimental medicine • Risk prediction • Cell therapies • CRF, CUBRIC, PET • New appointments in imaging

17. Clinical and Translational Genetic Epidemiology Genomics Functional Studies Epidemiology Translating Genetic Findings. • Build cell biology, proteomics, transcriptomics • Local expertise (HD) • Appointment of Derek Blake • Collaboration (BIOSI, G2C,Sanger) • Bioinformatics • Animal models • Wilkinson, Isles, Humby • Killcross/Walters • Dunnett • Evans/ Clarke • Sanger/G2C • Brain tissue • Current collections • Prospective collections

18. Clinical and Translational Genetic Epidemiology Genomics Functional Studies Epidemiology Translating Genetic Findings. • Increased focus on G*E interplay in origins and outcomes of developmental disorders • CGenic • ALSPAC • Psychosis • Addiction • Dyslexia • Welsh population • CRCC Cymru plus networks-MHRN, NeuroDem etc • Biobank

19. Summary • Currently major focus on identifying risk genes • Increasing focus on downstream work • Many areas for potential involvement of other CU groups