Understanding Genetics of Schizophrenia Carlos N Pato M

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

Lifetime Risk for 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)

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

Phenotype Definition E A F J C D G B H

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

Schizophrenia on Chromosome 5 q

Region rich in candidate genes • Glutamate receptor-GRIA 1 • GABA cluster-GABRA 1, GABRA 2 • Serotonin Receptor-HTR 4 • Glycine Receptor-GLRA 1 • Glucocorticoid receptor-NR 3 C 1 • Adrenergic receptor-ADRB 2 • Neuregulin-NRG 2 • Kinase-CAMK 2 A

Human Mapping Assay 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 Accuracy >99% AA BB AB

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.

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

Genome-wide Survey of CNVs Nature (2008) • On chromosome 22 q 11. 2 - identified deletions in ~0. 3% of schizophrenia patients (P =0. 00056 versus controls) • Odds ratio = 21. 6

Genome-wide Survey of CNVs Chromosome 22 deletion

Genome-wide Survey of CNVs Nature (2008) • On chromosome 15 q 13. 2 - identified deletions in ~0. 3% of schizophrenia patients (P =0. 00056 versus controls) • Odds ratio= 17. 9

Genome-wide Survey of CNVs Chromosome 15

Genome-wide Survey of CNVs Nature (2008) • On chromosome 1 q 21. 1 - identified deletions in ~0. 3% of schizophrenia patients (P =0. 0. 024 versus controls) • Odds ratio= 6. 6

Genome-wide Survey of CNVs Chromosome 1

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

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

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

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