disease susceptibility

Question 1

what type of genetic risk associated with schizophrenia

Answer 1

polygenic model

Question 2

Disturbances in _ and _ systems points to role for polymorphisms in these systems in determining susceptibility to schizophrenia

Answer 2

dopaminergic
5HT (serotonin)

Question 3

what studies are used to study schizophrenia susceptibility and what did it show

Answer 3

family and case control
- linage studies suggested the existence of susceptobility loci on up to 11 chromosomes

Question 4

What genes are linked to schizophrenia susceptibility

Answer 4

□ ZNF804A-probable transcription factor (first gene identified in a GWAS)
□ Other transcription factors (eg. KLF6)
□ Various genes relevant to calcium signalling and glutamate signalling (eg. ATP2A2, which encodes a calcium pump). Variants in ATP2A2 also associate with bipolar disorder.
□ Genes involved in synaptic function

Question 5

what was the result of a large GWAS of schizophrenia

Answer 5

74776 cases and 101023 controls (>7.5 million SNPs)
- 313 independent signals at 263 distinct loci
- ACE risk variant associates with low Angiotensin-converting enzyme (ACE) expression

Question 6

how is ACE linked to the CNS

Answer 6

• ACE is a dipeptidyl-carboxy oligopeptidase located on the cellular membrane of neurons
• Involved in neurosignalling via its ability to catalyse the degradation of several neuro peptide substrates,
  such as bradykinin (BK), neurotensin (NT), substance P, enkephalins (EKs)
• ACE has several functions in the CNS and is implicated in other phenotypes.
  Eg. levels associate with cognitive function and Alzheimers Disease

Question 7

how is CYP2D6 and schizophrenia linked

Answer 7

-though the mechanism of linkage is unknown
-association signals localises to CYP2D6
-multiple functional variants = such as exon 3 skipping and numerous linked SNPs

Question 8

how many anti-psychotic drugs does CYP2D6 metabolises

Answer 8

metabolises 40% of anti-psychotic

Question 9

early onset alzheimers disease is often _ disorder

Answer 9

single gene/monogenic

Question 10

late onset Alzheimer is more _ than early and shows only _ clustering within families

Answer 10

common, modest

Question 11

which gene locus has been identified as a susceptibility locus from family studies of alzheimers

Answer 11

apolipoprotein E (APOE)

Question 12

What was the result of the GWAS on Alzheimers disease

Answer 12

36 risk loci identified
HAVCR2 accumulates in aged microglia and binds precursor beta (amyloid protein)
BIN1 variant associates with endosome-size deregulation (an early biomarkers for AD)

Question 13

what is apolipoprotein E

Answer 13

mediates transfer of cholesterol and phospholipids between cells and is important for injury repair in the brain

Question 14

how are the variants of APOE different

Answer 14

E2 = protective
E2 -> E3 = Cys->Arg at 158
E3 -> E4 = Cys ->Arg at 112

Question 15

what is the differece between APOE2 and APOE4

Answer 15

2 = lower chloesterol and higher APOE protein compared to 4

Question 16

why is APOE4 a risk factor for alzheimers

Answer 16

due to the facilitating accumulation of b-amyloid protein in the brain

Question 17

people who are APOE4 homozygoous are almost certain to develop Alzheimers by what age

Answer 17

80

Question 18

the overall contribution of the APOIE locus to alzheimers susceptibility is approximately what ?

Answer 18

50%

Question 19

what was the result when APOE was genotyped to predict the clinical response to tacrine

Answer 19

acrine – an acetylcholinesterase inhibitor
APOE4 carriers are less responsive to therapeutic acetylcholine inhibition

Question 20

how to treat APOE4 driven Alzheimers

Answer 20

• Rationale for gene therapy is to increase the expression of the protective APOE2 variant to overcome the effects of APOE4
• issue with homozygous

Question 21

What was the results of the twin studies and smoking

Answer 21

• indicates the importance of genetics in both the decisions to start smoking, continue and to quit
• Some genetic linkage studies have been performed on smoking behaviour

Question 22

True or False - smoking is mongenic

Answer 22

False - it polygenic (as is addiction)
however there is also cultural factors that contribute

Question 23

which CYP has been linked to smoking

Answer 23

• CYP2A6
• it is responsible for 90% of nicotine metabolism to cotinine (active metabolite)

Question 24

what are the 3 types variation of CYP2A6

Answer 24

Wildtype, Mutation and deletion of whole genes

Question 25

How is nicotinic acetylcholine receptor linked to smoking behaviour

Answer 25

□ Nicotine binds to neuronal nicotinic acetylcholine receptors (NACHRs) (which are at 62% occupancy 6hs after smoking)
□ triggers the release of dopamine which gives an emotional reward
□ A smoker’s brain doesn’t release more dopamine than a non-smoker’s brain. They release dopamine at different times and become dependent on nicotine for dopamine release.

Question 26

What was results of the GWAS study on smoking behaviour

Answer 26

significant association between smoking/cigarettes smoked per day and
□ Chr 15 CHRNA3-nicotinic acetylcholine receptor alpha subunit 3
□ Chr 8 CHRNA6 and CHRNB3
□ Chr 19 CYP2A6 and CYP2B6
Genes that encode nicotinic acetylcholine receptors & CYP2A6

Question 27

what is the polymorphims is associated with nicotine dependence and lung cancer

Answer 27

D398N polymorphism in exon 5 of CHRA5(15q25)

Question 28

what is the link between schizophrenia and lung cancer

Answer 28

Reverse causation - smokers are more likely to take up smoking to relieve anxiety.

Question 29

what is licensed to assist with smoking cessation

Answer 29

Antidepressant bupropion - Genotype for CYP2B6 affects metabolism of this drug and overall response