testimony
TRANSCRIPT
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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
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Lifetime Risk for Schizophrenia
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)
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Genes (DNA) do not read the DSM-IV.
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Phenotype Definition
A
C
H
D G
FE
J
B
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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
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Schizophrenia on Chromosome 5q
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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
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AA BB AB
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%Accuracy >99%
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Transcript probes with the highest diagnostic utility for distinguising BP, SCZ, and control subjects
Title Symbol LocationCDP-diacylglycerol--inositol 3-phosphatidyltransferase (phosphatidylinositol synthase) CDIPT 16p12.1chemokine (C-X-C motif) ligand 3 CXCL3 4q21chemokine (C-C motif) receptor 1 CCR1 3p21split hand/foot malformation (ectrodactyly) type 3 SHFM3 10q24KIAA0082 KIAA0082 6p21.2
The expression patterns of the 35 most predictive genes correctly classified all BP and control subjects and 27 of 33 SCZ subjects.
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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)
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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
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Genome-wide Survey of CNVsChromosome 22 deletion
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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
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Genome-wide Survey of CNVsChromosome 15
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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
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Genome-wide Survey of CNVsChromosome 1
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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
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• Common polygenic variation contributes to risk
• Rare variants likely to contribute to risk
• major histocompatibility complex strongly replicated association with schizophrenia
MHC and Common VariantsNature, 2009
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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
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Future Directions
• Gene identification
• Gene expression
• Proteomics
• Treatment development• At risk studies- with a focus on development of
pre-clinical diagnosis + treatment