Understanding Genetics of Schizophrenia

1. Understanding Genetics of Schizophrenia Carlos N. Pato, M.D. , Ph.D. Professor and Chair of Psychiatry Center for Genomic Psychiatry Keck School of Medicine University of Southern California

2. Schizophrenia 0.5-1.0% General Population 10-15% If a parent or sibling (including dizygotic twin) is schizophrenic 40% If both parents are schizophrenic 45-75% If monozygotic twin is schizophrenic (Same risk to children- Fisher) Lifetime Risk for Schizophrenia

3. Genes (DNA) do not read the DSM-IV.

4. Phenotype Definition Bipolar Disorder Schizophrenia E F A H J D G C B Psychosis

5. Genetic Strategies • What is linkage ? • What is a LOD score or a NPL ? • What is an association ? • How to understand statistical significance. • Candidate genes • Genome wide scans (genomic mapping) • Gene expression arrays

6. Schizophrenia on Chromosome 5q

7. Region rich in candidate genes • Glutamate receptor-GRIA1 • GABA cluster-GABRA1, GABRA2 • Serotonin Receptor-HTR4 • Glycine Receptor-GLRA1 • Glucocorticoid receptor-NR3C1 • Adrenergic receptor-ADRB2 • Neuregulin-NRG2 • Kinase-CAMK2A

8. A rapid, reliable and cost-effective assay for simultaneously genotyping many thousands of SNPs distributed across the genome Generic complexity reduction scheme Hybridization-based allele discrimination AA BB AB Human Mapping Assay Accuracy >99%

9. Transcript probes with the highest diagnostic utility for distinguising BP, SCZ, and control subjects The expression patterns of the 35 most predictive genes correctly classified all BP and control subjects and 27 of 33 SCZ subjects.

10. Genome-wide Survey of CNVsNature (2008) • 3380 patients with schizophrenia and 3139 ancestrally-matched controls • identified three regions • large (>500kb) deletions increase disease risk • Deletions easier to detect because of their size and replicability compared to single point mutations (single SNP)

11. Genome-wide Survey of CNVsNature (2008) • On chromosome 22q11.2 - identified deletions in ~0.3% of schizophrenia patients (P =0.00056 versus controls) • Odds ratio = 21.6

12. Genome-wide Survey of CNVsChromosome 22 deletion

13. Genome-wide Survey of CNVsNature (2008) • On chromosome 15q13.2- identified deletions in ~0.3% of schizophrenia patients (P =0.00056 versus controls) • Odds ratio= 17.9

14. Genome-wide Survey of CNVsChromosome 15

15. Genome-wide Survey of CNVsNature (2008) • On chromosome 1q21.1 - identified deletions in ~0.3% of schizophrenia patients (P =0. 0.024 versus controls) • Odds ratio= 6.6

16. Genome-wide Survey of CNVsChromosome 1

17. Genome-wide Survey of CNVsNature (2008) • In the same issue of Nature, a parallel paper by DeCode showed the same results • Extremely strong evidence for these relatively rare mutations • Proves the necessity for extremely large studies

18. MHC and Common VariantsNature, 2009 • Common polygenic variation contributes to risk • Rare variants likely to contribute to risk • major histocompatibility complex strongly replicated association with schizophrenia

19. Genomic Psychiatry Cohort • We have established the goal of studying 30,000 patients and 30,000 controls • Schizophrenia and Bipolar disorder • We have begun to bring together the funding for this large-scale program • The NIMH launched this program with an initial $25 million dollars in grants to USC and MGH/Broad

20. Future Directions • Gene identification • Gene expression • Proteomics • Treatment development • At risk studies- with a focus on development of pre-clinical diagnosis + treatment