What is the genetic basis bipolar disorder based on GWAS studies? Explain what they do and How is it treated?
- ANK3
- CACNA1C
- Proteins transcribed from these genes regulate inflow and outflow of ions during action potential
- Both are downregulated by lithium
- Lithium reduces transcription of protein
- Effective treatment of Bipolar
What is the correlaton between sample size of GWAS and associative markers found?
Strong correlation between the sample size of a GWAS and the number of associated/SNP markers discovered
- Larger samples provide more statistical power to detect small effects
Summarise the utilites of GWAS.
- Provide new evidence for existing hypothesis
- Raise new possibilites
- Point to environmental risk factors (2Cov (G,E))
Utility of GWAS: (1)?
- Provide new evidence for existing hypothesis: “Supports dopamine hypothesis”
- Schizophrenia previously linked to abnormal dopamine signalling
- Antipsychotic drugs block dopamine
- DRD2 (Dopamine-Receptor gene) is associated with schizophrenia
- Schizophrenia previously linked to abnormal dopamine signalling
Utility of GWAS: (2)?
- Raise new possibilites - “Does acquired immunity play a role in development of schizophrenia”
- Major Histocompatability Complex (MHC) has significant association (p < 10-30 ) with schizophrenia
- MHC genes code for cell-surface protein, allowing immune system to recognise foriegn substances
- MHC genes also play other roles in nervous system
- Major Histocompatability Complex (MHC) has significant association (p < 10-30 ) with schizophrenia
Utility of GWAS: (3)?
- Point to environmental risk factors (2Cov (G,E)) - “Association of schizophrenia with CHRAN5-A3-B4 variants suggest heavy smoking may contribute to schizophrenia risk”
- Variants in CHRNA5-A3-B4 gene cluster known to be associated with smoking
- Encode subunits of nicotinic acetylcholine receptors
- Variants in CHRNA5-A3-B4 gene cluster known to be associated with smoking
- Smoking has >80% prevalance among Schizophrenic pateints
What are some properties of psychiatric disorders?
- Complex G × E interactions
- Diagnostic categories
- Difficult to define 2 individuals can have same diagnostics without overlapping symptoms
- Interference from multiple deficits
- Not a pure deficit
What are some properties of endophenotypes?
- More immediate relationships
- Trait (Single) against Biology
- Single quantitative traits - Precision
- Don’t need diagnostics
- Psychologically normal participants
- Not just clinical. No interference from other deficits
What is a cognitive measure discussed in the lecture?
Wisconsin Card Sorting Test
- Change rules (Number/Colour/Shape)
- Examine cognitive flexibilty to deal with this
What is a neurophysiological discussed in the lecture?
Pre-pulse inhibition of startle response
What is a psychomotor measure discussed in the lecture?
Antisaccade oculomotor task
- Examine ability to inhibit temptation to follow the dots
- Visual mechanism
What has disturbances of visual senstiivty been associated with. What has GWAS found (on endophenotypes)?
Disturbances of visual sensitivity are associated with both schizophrenia and autism
- In a GWAS of visual sensitivity in a psychologically healthy population, the strongest association signal was at a marker on chromosome 1q21.1*
- Region 21.1 of the long (q) arm of chromosome 1
- Situated in the 5′-untranslated region of the gene PDZK1
- Functional SNP is at 5’-untranslated region, affects transcription rather than protein structure
- Known risk region for both schizophrenia and autism
What does PDZ protein do and PDZK1 interact with?
PDZ proteins
- Hold other proteins in appropriate configuration for localisation on the surface of cells
PDZK1
- Interacts with NMDA receptors
- Contrast gain control in retina
- Perceptual abnormalities in schizophrenia have been suggested to arise from NMDA receptor dysfunction
- Interacts with DLG4
- Disruption of Dlg4 in mouse produces an ASD-related phenotype
What is the conclusion based on the finding of perceptual abnormalities in SZ and Autism?
- Perceptual abnormalities observed in the 2 disorders may be linked by common genetic elements that affect synaptic function
Endophenotypes vs Diagnostics?
Endophenotypes
- Yield larger genetic effects than diagnoses
- Avoids difficulties assigning diagnostic categories
- Allows testing of psychologically normal participants
- Underlying biological mechanisms are likely to be simpler for endophenotypes than for psychological disorders
What is forward genetics in animal models?
Forward-genetic approach
- Random mutations are induced
- Mutagenised animals crossed with a wild-type strain over several generations
- Animals are screened for the target phenotype
- Animals with the target phenotype are genotyped
What is a finding of foward-genetics discussed? As well as implication of the finding?
- Postiive correlaion between neural complexity and length of life cycle
- Hence, techniques relying on breeding multiple generations are not fesible in complex species (humans)
What is reverse genetics in animal models?
Reverse-genetic approach
- Target mutations are induced
- Effect on phenotype is measured
What is a usage of revese-genetics?
- CRISPR-Cas9 System
- Bacterium’s natural defence against invading viruses
- Used this system to create targeted genetic mutations in model organisms
- Cas9: Nuclease protein (cut nucleotide/DNA)
- Guide RNA directs Cas9 protein to desired DNA sequence, where Cas9 cuts DNA
- RNA guides the system to a location in the genome that matches its target sequence.
- Random repair process can
- (a) disable the gene
- (b) introduce target sequence to be inserted during repair
