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Unformatted text preview: ference in percentage
from that which would be expected in
the general population, challenging the Causes: III. Incomplete concordancewhat does that really mean?
Even with monozygotic
twins concordance rate is a
only about 50%.! ! Being a relative does not
capture half of the ! ! genetic? !
or environmental? !
or both? ! ! mechanisms at work.! ! Prevalence stable across
cultures and continents…! ! Prominent susceptibility genes as indicated by reliable neuronal markers
of schizophrenia I. Cortical GABAergic interneurons Chandelier cells and number
of GABAergic contacts
reliably decreased by 40%
in PFC of schizophrenics;
Woo et al., PNAS 1998,
95:5341-6) Prominent susceptibility genes as indicated by reliable neuronal markers of
schizophrenia II. Calcium channels. III. Metabotropic glutamate receptors Emerging Genetic Evidence on Complex Brain Disorders Converges on Speciﬁc Molecular
(A) Multiple subunits of voltage-gated calcium channels are among the genome’s strongest
associations to schizophrenia and bipolar disorder. !
(B) Genes encoding the postsynaptic components of excitatory synapses are implicated by
both rare and common variants in schizophrenia.
!18 Susceptibility genes impair synaptic
functions and plasticity Harrison and Weinberger, Molecular Psychiatry 2005, 10:40-68 Causes: genetic vs nongenetic?
• Concordance rate for identical twins: 48%
• Fraternal (dizygotic) twins: 17%
• Multiple (even thousands) susceptibility genes.
• Incidence rate: stable across continents, cultures, socioeconomic
• Efforts to identify viral and other obvious causes were not or not
reliably substantiated by massive longitudinal studies.
• BUT: Obstetric complications, maternal infections etc.: early insults
that can affect brain development, or interactions with genetic
• Concordance rate: truly reflecting environmental variables or
hitherto unknown genomic mechanisms for bestowing genetic
vulnerability? (such as epigenetic, copy number variations,
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- Fall '08