W12L1 - Genetics 2

Question 1

What is the genetic basis bipolar disorder based on GWAS studies? Explain what they do. How is it treated?

Answer 1

• 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

Question 2

What is the correlaton between sample size of GWAS and associative markers found

Answer 2

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

Question 3

Summarise the utilites of GWAS

Answer 3

1. Provide new evidence for existing hypothesis
2. Raise new possibilites
3. Point to environmental risk factors (2Cov (G,E))

Question 4

Utility of GWAS: (1)

Answer 4

• 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

Question 5

Utility of GWAS: (2)

Answer 5

• 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

Question 6

Utility of GWAS: (3)

Answer 6

• 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
• Smoking has >80% prevalance among Schizophrenic pateints

Question 7

What are some properties of psychiatric disorders

Answer 7

• 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

Question 8

What are some properties of endophenotypes

Answer 8

• 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

Question 9

What is a cognitive measure discussed in the lecture

Answer 9

Wisconsin Card Sorting Test

• Change rules (Number/Colour/Shape)
  
  • Examine cognitive flexibilty to deal with this

Question 10

What is a neurophysiological discussed in the lecture

Answer 10

Pre-pulse inhibition of startle response

Question 11

What is a psychomotor measure discussed in the lecture

Answer 11

Antisaccade oculomotor task

• Examine ability to inhibit temptation to follow the dots
  
  • Visual mechanism

Question 12

What has disturbances of visual senstiivty been associated with. What has GWAS found (on endophenotypes)

Answer 12

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

Question 13

What does PDZ protein do and PDZK1 interact with?

Answer 13

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

Question 14

What is the conclusion based on the finding of perceptual abnormalities in SZ and Autism

Answer 14

• Perceptual abnormalities observed in the 2 disorders may be linked by common genetic elements that affect synaptic function

Question 15

Endophenotypes vs Diagnostics

Answer 15

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

Question 16

What is forward genetics in animal models

Answer 16

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

Question 17

What is a finding of foward-genetics discussed. As well as implication of the finding.

Answer 17

• Postiive correlaion between neural complexity and length of life cycle
  
  • Hence, techniques relying on breeding multiple generations are not fesible in complex species (humans)

Question 18

What is reverse genetics in animal models

Answer 18

Reverse-genetic approach

• Target mutations are induced
• Effect on phenotype is measured

Question 19

What is a usage of revese-genetics

Answer 19

• 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