Genetics and Translational Psychiatry

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Genetics and Translational Psychiatry

• Mike Owen
• Dept Psychological Medicine
• School of Medicine.

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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 ODonovan, 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.
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Mission

• Using genetics and genomics to inform our
  understanding of the aetiology, pathogenesis,
  classification and treatment of the major
  psychiatric and neurodegenerative disorders.

Clinical and Translational
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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.

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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.

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Major Themes

• Psychosis and Major Affective Disorders
• Blake, Craddock, Jones I, Killcross, Kirov,
  ODonovan, Owen, Wilkinson, Williams N, Zammit.
• Neurodegenerative Disorders
• Blake, Dunnett, Jones, L, Morris, ODonovan,
  Owen, Rosser, Williams, J.
• Developmental Disorders
• Craddock, Harold, Hay, Jones I, Killcross, Kirov,
  ODonovan, 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

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Psychosis and Major Affective Disorders

• 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).
• GE 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.

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Neurodegenerative Disorders

• Alzheimers disease positional genetics (MRC
  Programme, WT project, ART Centre).
• Alzheimers disease proteomics (AS)
• Huntingtons disease transplantation, comparative
  molecular pathology (MRC Programme, MRC, HighQ,
  EU).
• Parkinsons 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 Alzheimers 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 Huntingtons
  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.

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Developmental Disorders

• 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.

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Mouse Behavioural Genetics/Epigenetics

• 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.

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• 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.

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Future Strategy
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Future Strategy Genetic Epidemiology.

• GE interplay
• Developmental psychopathology, substance
  abuse/addiction
• Role of prenatal environment
• Collaboration with PSYCHOL
• Development of resources
• CASTANET, ALSPAC

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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.

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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

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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

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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

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Translating Genetic Findings.

• Increased focus on GE interplay in origins and
  outcomes of developmental disorders
• CGenic
• ALSPAC
• Psychosis
• Addiction
• Dyslexia
• Welsh population
• CRCC Cymru plus networks-MHRN, NeuroDem etc
• Biobank

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Summary

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