WHY?

1. NEW SCIENCE AND THERAPIES FOR PATIENTS WITH MENTAL ILLNESS Now is the most promising time in the past two decades for mental health research WHY?

2. PAST INVESTMENTS IN BASIC RESEARCH Basic neuroscience • Mental illness is a biological brain disease • Medicines in development based on basic neuroscience research Human genetics • A new era has dawned for understanding complex human genetic diseases • Fostering new approaches to treatment and diagnosis • Example from autism spectrum disorder

3. How can we come to understand the underlying molecular causes of schizophrenia and bipolar illness? The single largest risk is the sequence of a patient’s genes

4. Dizygotic twins Schizophrenia Monozygotic twins Bipolar disorder 0 20 40 60 80 100 Concordancerate Twin studies support a strong genetic component Gottesman 1991

5. Parents Siblings Bipolar disorder Children Schizophrenia Half-siblings Grandchildren Nephews/Nieces Aunts/Uncles General population 10 0 5 15 20 Lambda Families are at an increased risk Tsuang and Faraone 1990

6. Dad B b B Bb BB Mom b Bb bb GENETIC MAPPING Mendelian genetic diseases: rare variants Determinative mutations; strong effects High penetrance: % of people with the gene that get the illness is high >2000 discovered in humans Tracing gene transmission in families

7. Mendeliandisease DNA-based frequency variants and disease susceptibility Penetrance of disease High Intermediate Modest Low Frequency of DNA variation in population Very rare Rare Uncommon Common McCarthy et al., Nat Genet Rev 2008

8. Map of Orlando — state level

9. Mendeliandisease Low-frequency variants with intermediate penetrance Variants identifiable by whole-genome association studies Hard to identify genetically DNA-based frequency variants and disease susceptibility Penetrance of disease High Complex genetic disease Intermediate Modest Low Frequency of DNA variation in population Very rare Rare Uncommon Common McCarthy et al., Nat Genet Rev 2008

10. COMPLEX GENETIC DISEASES Multiple genes • Common variants, small effects each gene; rare gene variants, stronger effects • Additive effects lead to risk of illness Need large patient samples • Using most sophisticated methods available in human genetics

11. How many samples are needed? • 30,000 each from patients with: • Schizophrenia • Bipolar disorder • Controls

12. Number of Cases and Controls in the Study Rare Rare Rare 1,000 5,000 10,000 30,000 15% increased risk Good Power Common Common Common No Power 20% increased risk 30% increased risk Power to detect in a psychiatric genetics study

13. Large, collaborative whole-genome studies ~70% of data or ~6 billion genotypes produced at the Stanley Center/Broad Institute Bipolar disorder 3 studies combined ~4,400 cases, ~6,200 controls Schizophrenia 7 sites combined ~3,500 cases, ~3,500 controls Wellcome Trust Case Control Consortium

14. Variants identifiable by whole-genome association studies DNA-based frequency variants and disease susceptibility Penetrance of disease High Intermediate Modest Low Frequency of DNA variation in population Very rare Rare Uncommon Common McCarthy et al., Nat Genet Rev 2008

15. Map of Orlando — city level

16. WHAT MAKES THIS POSSIBLE? • Sequence of human genome • Dense map of markers or signposts across the genome — like signs along the highway • Methods for measuring signs or markers that allow for measurement of 1–2 million markers at once in an individual human sample of DNA • Computer programs allow interpretation of results • Methods only 2+ years old

17. METHOD FOR STUDYING COMPLEX GENETICS Association study • Search for markers in populations, not families

18. Affecteds Controls Association studies Where effects are probabilistic, must compare frequencies in cases and controls

19. 8 6 4 Probability assessment 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Chromosome Whole-genome study of 4400 bipolar cases Statistical assessment of gene findings Cases 4434 Controls 6214 Manuel Ferreira, Yan Meng

20. ANK3: Ankyrin G • Coordinates large protein complexes at specific membrane sites • Neuronal sodium channels • Potassium channels • Lamotrigine used to treat bipolar disorder Bennett et al. (2008) CACNA1C: L-type, voltage-gated calcium channel, alpha1c subunit • Calcium channel blockers have been used to treat bipolar disorder Bidaud et al. (2006)

21. “ The cardinal feature of heritable ion channel disease is a periodic disturbance of rhythmic function in a constitutionally hyperexcitable tissue. ” Biological implications of genetic findings Gargus, Biological Psychiatry 2006

22. FINDINGS THUS FAR IN SCHIZOPHRENIA Association findings Novel gene deletions

23. 8 6 Probability assessment 4 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Chromosome Whole-genome study of 3400 schizophrenia cases Statistical assessment of gene findings Cases 3414 Controls 3625 Jennifer Stone

24. Deletions of genes in schizophrenia • An excess of DNA deletions in genes in samples of patients vs. controls • Per patient very small increase • Biological implications being evaluated will be clues to underlying causal pathways

25. Variants identifiable by whole-genome association studies DNA-based frequency variants and disease susceptibility Penetrance of disease High Intermediate Modest Low Frequency of DNA variation in population Very rare Rare Uncommon Common McCarthy et al., Nat Genet Rev 2008

26. Low-frequency variants with intermediate penetrance Hard to identify genetically DNA-based frequency variants and disease susceptibility Penetrance of disease High New methods rapidly developing Intermediate Modest Low Frequency of DNA variation in population Very rare Rare Uncommon Common McCarthy et al., Nat Genet Rev 2008

27. Map of Orlando — street level

28. NEW TECHNOLOGIES FOR GENETICS • High-throughput DNA sequencing: ability to sequence all genes in 1000 patient samples and 1000 controls • More detailed map of the human genome • Next 2–5 years WILL see this technology

29. Mendeliandisease Low-frequency variants with intermediate penetrance Variants identifiable by whole-genome association studies Hard to identify genetically DNA-based frequency variants and disease susceptibility Penetrance of disease High Intermediate Modest Low Frequency of DNA variation in population Very rare Rare Uncommon Common McCarthy et al., Nat Genet Rev 2008

30. IMPORTANT REALIZATION • Science’s ability to unravel the underlying causes of severe mental illness is upon us • Technologies are rapidly progressing • What is limiting? Not the intellectual approach • For the first time in the history of the field there is a way forward that can lead to significantimprovements in diagnosis and therapy

31. Largest treatment studies 1 Lieberman et al., N Engl J Med, 2005; 353:1209–1223. 2 Trivedi et al., Am J Psychiatry, 2006; 163 :28–40. 3 Perlis et al., Am J Psychiatry, 2006; 163: 217–224. 4 Leucht et al., Mol Psychiatry, 2008; 1–19.

32. GENETIC DISCOVERY TO TREATMENT • Many examples of discovering genetic predispositions to disease and translating the discoveries into important, new treatments • As technology for discovering genes for disease have evolved, technologies for translating the discoveries into treatments have also evolved

33. Impact of genetics on biomedicine • Discovery of drug targets: • Statins and HMG Coa reductase • Proscar and benign prostatic hyperplasia (5-alpha reductase) • Gleevec and CML (aberrant kinase) • Herceptin antibody to Her2 for breast cancer • New approaches to Alzheimer’s

34. Approaches to therapy: other illnesses • Fragile X syndrome: • a disease of abnormal brain development • molecular defect known • animal models created based on human defect • abnormal physiology clarified • new treatments discovered based on abnormal physiology • good results in animal model with human defect • in early development for humans • mGluR5 antagonists

35. Identify risk genes Develop cell-based assays Develop mouse model with a quantifiable phenotype; a consequence of variant gene Identify chemicals that reverse cell-based and animal-based phenotype Human trials in genetically defined variant Test in broader group of patients with the illness Paradigm for new treatments for autism, bipolar disorder, and schizophrenia Understand functional consequences of variant gene

36. Possible new drugs in development • Glu 2,3 agonist • D-cycloserine • Desmethyl clozaril • M1 allosteric agonists • Gaba alpha 2,3 agonists • PDE-10 inhibitors • Alpha-7 nicotinic agonists

37. Drug mechanism Stage of research mGlur2,3 agonist Expanded human trials Desmethyl clozaril Human trials Alpha-7 nicotinic receptor agonist Human trials Gaba alpha 2,3 agonist Early human trials New approaches to therapy

38. New approaches to therapy Drug mechanism Stage of research D-cycloserine: novel regimen, use with psychotherapy Proven in acrophobia,anxiety Phosphodiesterase 10 inhibitors Animal research,excellent results

39. SUMMARY OF WHERE WE ARE • Significant progress on new therapies is possible, even in genetically determined disease where development of the brain is awry • Significant progress toward identifying underlying causes of schizophrenia, bipolar disorder, and autism, with genetic technologies evolving rapidly • The coming 5–10 years willlead to a much greater understanding of molecular basis for these and other related disorders

40. What will this mean for patients? • Much better diagnostic tools, clearer categories of diagnosis, and more personalized therapy • Many new targets for new medicines

41. Mendeliandisease Low-frequency variants with intermediate penetrance Variants identifiable by whole-genome association studies Hard to identify genetically DNA-based frequency variants and disease susceptibility Penetrance of disease High Complex genetic disease Intermediate Modest Low Frequency of DNA variation in population Very rare Rare Uncommon Common McCarthy et al., Nat Genet Rev 2008

42. IMPORTANT REALIZATION • Science’s ability to unravel the underlying causes of severe mental illness is upon us • Technologies are rapidly progressing • What is limiting? Not the intellectual approach • For the first time in the history of the field there is a way forward that can lead to significantimprovements in diagnosis and therapy