Behavioural & psychiatric genetics II: L23

Question 1

GWAS

1. meta analysis of bipolar disorder found
2. the proteins described from both these genes regulate
3. both genes are
4. lithium is

Answer 1

1. associations with the genes (1) ANK3 & (2) CACNA1C
2. the flow of ions in & out of neurons during an action potential
3. down-regulated by lithium
   (-> lithium reduced transcription of the protein)
4. an effective treatment for BP

Question 2

GWAS

1. there is a strong correlation between the

Answer 2

1. sample size of a GWAS and the number of associated markers discovered
   - > larger samples provide more statistical power to detect small differences

(the more people that are test, the more stuff we find = increased statistical power)

Question 3

1. GWAS can provide new evidence for
2. GWAS can raise new
3. what do MHC genes code for

Answer 3

1. existing hypotheses
   - > schizophrenia previously been linked to abnormal dopamine signalling
   - > antipsychotic drugs block dopamine receptors
2. possibilities
   - > most significant association is the ‘major histocompatibility complex’ (MHC)
3. cell-surface proteins that allow the immune system to recognise foreign substances
   - > raises the question: does acquired immunity play a role in the aetiology of schizophrenia?

N.B= MHC proteins do play other roles in the nervous system

Question 4

1. GWAS can point to what other kind of risk factors
   - > examples
2. Schizophrenia and smoking

Answer 4

1. environmental
   - > variants in the CHRNA5 - A3 - B4 gene cluster are known to be very strongly associated with heavy smoking
   - > they encode subunits of a nicotinic acetylcholine receptor, cholinergic receptors that also respond to nicotine
2. 80% prevalence among people with schizophrenia
   - > association of schizophrenia with CHRNA5-A3-B4 variants suggest heavy smoking may contribute to schizophrenia risk (genes + environment)

Question 5

1. Psychological disorders are a complex interaction between
2. diagnostic categories can be
3. interference from

Answer 5

1. genes & environment
2. very hard to define
3. multiple deficits = not a pure measurement

Question 6

Endophenotypes

1. definition
2. advantages

Answer 6

1. separate behavioural symptoms into more stable phenotypes with a clear genetic connection
2. • more immediate/ direct relationships ( simpler genetic bases than the disorder)
     - single quantitative traits
     - study in psychologically normal participants ( not only present in individuals affected by the disorder)

Question 7

Endophenotypes of psychological disorders:

1. cognitive measures
2. neurophysiological measures
3. psychomotor measures
4. anomalies of basic visual perception

Answer 7

1. Wisconsin card sorting test (match cards based on shape, colour, number) = measures time taken to change
2. pre-pulse inhibition of startle response
3. Antisaccade oculomotor task (schizophrenia) ability to inhibit automatic response to follow dot
4. neural mechanisms particularly well characterised

Question 8

1. manhattan plot is the way we visualise
2. a pedigree chart is the
3. a karyotype map

Answer 8

1. results of a genome-wide association study
2. family-tree-like map used to trace a trait through generations
3. see abnormalities in the appearance of the chromosome (e.g. fragile x syndrome)

Question 9

1. disturbances of visual sensitivity are associated with
2. in a GWAS of visual sensitivity in a psychologically healthy population the strongest association signal was
3. if the functional SNP is situated in the 5 untranslated region of gene PDZK1, it likely affects

Answer 9

1. schizophrenia (gene PDZK1) and autism
2. at a marker on chromosome 1q21.1
   - > known risk region for both schizophrenia and autism spectrum disorders
3. protein transcription rather than structure

Question 10

1. PDZ proteins hold other proteins in
2. PDZK1 interacts with (2)
3. perceptual abnormalities are observed in 2 different disorders which may be linked by

Answer 10

1. appropriate configuration for localisation on the surface of cells
2. (1) NMDA receptors:
   - NMDA plays critical role in contrast gain control in the retina
   - perceptual abnormalities in schizophrenia have been suggested to arise from NMDA receptor dysfunction
   (2) DLG4
   - disruption of DLG4 in mouse produces an ASD- related phenotype
3. common genetic elements that affect synaptic function

Question 11

1. Endophenotypes of psychological disorders can yield

Answer 11

1. larger genetic effects than diagnoses
   - avoids difficulties assigning diagnostic categories
   - allows testing of psychologically normal participants
   - underlying biological mechanisms are likely to be simpler than for psychological disorders

Question 12

Forward genetics

1. in forward genetic approach
2. the mutagenised animals are crossed with a
3. animals are screened for
4. animals with the target phenotype are

Answer 12

1. random mutations are induced
2. wild-type strain over several generations
3. the target phenotype
4. genotyped

Question 13

Reverse genetics

1. in reverse genetic approach

Answer 13

1. targeted mutations are introduced and the effect on the phenotype is measured

Question 14

1. The CRISPR-Cas9 system is
2. it can be used to
3. Cas9 is a
4. guide RNA
5. this random repair process can

Answer 14

1. a natural part of a bacterium’s defence against invading viruses
2. create targeted (reverse genetics) mutations in model organisms
3. nuclease protein (cuts chains of nucleotides
4. directs the Cas9 protein to the desired DNA sequence, where the Cas9 cuts the DNA
5. disable the gene, or targeted sequence can be introduced to be inserted during repair