Genetics of Schizophrenia Flashcards
Schizophrenia ranks __th in global burden of illness
9
Schizophrenia is often co-morbid with….
drug dependence such as alcohol, nicotine, cannabis and cocaine as well as medical conditions such as obesity and Type 2 DM
Lifespan for schizophrenics is approximately
15 years less than general population
Previously thought that imbalance in _____ was cause of Schizophrenia but new findings suggest its to do with _____ and its action on ____ receptor
dopamine
glutamate
NMDA
Schizophrenia is due to both ________ and ______ risk factors however ________ is the biggest risk factor.
environmental
genetic
genetics
What are some examples of environmental risk factors?
- Time/ place of birth
- Infection e.g rubella
- Prenatal e.g. bereavement
- Obstetrics e.g CNS damage
Paternal age _____ risk. This is because of
increase
repeated cell devision where spermatogenesis is a main source of de novo mutations in the germline
What can genetics tell us about schizophrenia?
- Many genes involved in conferring schizophrenia risk
- More new mutations in people with schizophrenia
- Most genes indicate that neuronal dysfunction and neurodevelopmental pathways are involved in schizophrenia
- Depending on genotype, individuals can either be more or less likely to respond to certain antipsychotic drugs
Individuals with schizophrenia carry more new mutations that you would expect. There is a greater number of ___ and new mutations (i.e____________)…
rare
not present in either parent.
across the genome in Schizophrenia, both SNPS (single nucleopeptide polymorphisms) and CNV (copy number variants)
The same CNVs involved in Schizophrenia are also involved in
other neurodevelopmental disorders e.g. mental retardation, epilepsy and autism
What are the current models of neuronal dysfunction?
- Dopamine hypothesis
- Glutamate hypothesis
- Immunological theory
- Membrane hypothesis
- Neurodevelopment hypothesis
Schizophrenia is the overactivity of which pathway?
Mesolimbic
In brief, Dopamine theory is that there is
overstimulation of dopaminergic pathways in the limbic and cortical areas
In brief, Glutamate hypothesis is that there is
NMDA receptor hypofunction
What is the dopamine theory? (in detail)
Schizophrenia is due to excessive dopamine neurotransmission
The evidence:
- Psycho-stimulant drugs (e.g amphetamine, cocaine, L-DOPA) mimic positive symptoms of schizo
- Found excessive release of dopamine from striatum in high risk psychosis patients, as well as those experiencing their first psychotic episode
- Antipsychotics block D2 receptor and thus stop psychotic events
- Dopamine receptor gene variants associated with Sz
- PROBLEM: fails to describe some of the negative symptoms
What is the glutamatergic hypothesis?
Sz is associated with reduction in glutamate activity or GABA/glutamate imbalance.
The evidence:
- Used PCP and ketamine which mimics both positive and negative symptoms
- They block the NMDA (glutamate) receptor
- Glutamatergic pathways associated with SZ
- can disrupt cognition and ability to process sensory info correctly
What are some susceptibility genes for Sz?
- COMT
- REELIN
- DISC 1
- G 72
- Dysbindin
Immunological theory says that ______ activation or altered ________ may cause Sz
microglial
astrocytes
Astrocytes: Possible altered process - Altered glycogen metabolism
Altered glutamate metabolism and synaptic function
Astrocytes: Possible altered process - Altered release of neurotransmitters
Altered synaptic transmission
Astrocytes: Possible altered process - Altered release of trophic factors
Altered synaptic functions
Astrocytes: Possible altered process - Altered release of cytokines
Altered neuronal function
Some studies show that prenatal _______ caused by influenza virus in 2nd trimester may be cause of Sz. This is due to ______ activation
inflammation
microglial
