Understanding Genetics of Schizophrenia

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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
Bipolar Disorder
Schizophrenia
E
F
A
H
J
D
G
C
B
Psychosis
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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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Human Mapping Assay

• A rapid, reliable and cost-effective assay for
  simultaneously genotyping many thousands of SNPs
  distributed across the genome

Accuracy gt99
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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.
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Genome-wide Survey of CNVsNature (2008)

• 3380 patients with schizophrenia and 3139
  ancestrally-matched controls
• identified three regions
• large (gt500kb) 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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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

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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