The Genetics of Schizophrenia

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The Genetics of Schizophrenia
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The Genain quadruplets

• Identical quadruplets
• (Nora, Iris, Myra and Hester)
• All diagnosed with schizophrenia but with
  different symptoms (Kraepelinian subtype)
• Family history of psychiatric problems
• History of obstetric complications

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The Genetics of Schizophrenia

• Is there a genetic contribution to schizophrenia?
• What is heritable?
• Have we found any genes yet?

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Is there a genetic contribution to schizophrenia?

• Kraepelin and Bleuler the originators of the
  terms dementia praecox and schizophrenia both
  believed schizophrenia was heritable.
• An inherited predisposition to mental
  disturbances was apparent in approximately
  seventy percent of those case in which data could
  be evaluated Kraepelin (1899)
• heredity plays its role in the etiology of
  schizophrenia, but the extent and kind of its
  influence cannot as yet be stated (Bleuler, 1950)

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Family studies

• Familiarity not the same as Genetic
• Need to consider shared family environment as
  explanation.
• Twin studies
• Adoption studies

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Twin studies

• First twin studies in 1928 (Luxenberger)
• Now more than 20
• 5 recent studies from 1995 reviewed in 2000
• Combined 50 MZ and 4.1 DZ concordance
• Heritability 88

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Adoption studies

• High Risk Adoptees
• Adopted away children of schizophrenic parents.
• Adoptees family approach
• Risk of disease in relatives of schizophrenic
  adoptees compared to control adoptees.
• 5 vs 0.4 Danish studies

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Family studies
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The Genetics of Schizophrenia

• Complex disorder
• Single gene with sibling relative risk (ls) gt 3
  unlikely, more likely 2-3 loci with ls lt 2
• High heritability compared to other disorders
• Schizophrenia (85), breast cancer (30), type II
  diabetes (26)

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What is heritable?

• Symptoms
• Wide variation in symptoms of schizophrenia
• Overlap with other psychiatric disorders
• Especially schizoaffective disorder
• Endophenotypes

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Endophenotypes

• Sensory Motor Gating and Eye-Tracking Dysfunction
• Working Memory

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Genes for Schizophrenia?

• Dysbindin
• Neuregulin 1
• Catechol-O-methyltransferase
• D-amino acid oxidase activator
• Regulator of G-protein signalling 4
• DISC1
• Etc.

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Candidates
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Dysbindin (Dystrobrevin binding protein1)

• Positional candidate
• Several positive studies
• Component of the dystrophin-associated protein
  complex
• Component of PSD (esp hippocampus mossy fibres)

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Dysbindin candidate gene?

• Inconsistencies with associated alleles and
  haplotypes

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Dysbindin candidate gene?

• Haplotype does not explain all the linkage signal
• No functional variant identified

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Neuroregulin

• Positional candidate
• Large gene (1.5Mb) with multiple functions (cell
  signalling, ErbB receptor binding, axon guidance,
  etc)
• Associated haplotypes do not account for all the
  linkage signal
• No functional variant identified

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A synaptic model of schizophrenia

• Many (if not all) schizophrenia candidate genes
  code for proteins of the synapse
• Is a cellular model for schizophrenia possible?

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