disease susceptibility Flashcards
what type of genetic risk associated with schizophrenia
polygenic model
Disturbances in _ and _ systems points to role for polymorphisms in these systems in determining susceptibility to schizophrenia
dopaminergic
5HT (serotonin)
what studies are used to study schizophrenia susceptibility and what did it show
family and case control
- linage studies suggested the existence of susceptobility loci on up to 11 chromosomes
What genes are linked to schizophrenia susceptibility
□ 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
what was the result of a large GWAS of schizophrenia
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
how is ACE linked to the CNS
- 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
how is CYP2D6 and schizophrenia linked
-though the mechanism of linkage is unknown
-association signals localises to CYP2D6
-multiple functional variants = such as exon 3 skipping and numerous linked SNPs
how many anti-psychotic drugs does CYP2D6 metabolises
metabolises 40% of anti-psychotic
early onset alzheimers disease is often _ disorder
single gene/monogenic
late onset Alzheimer is more _ than early and shows only _ clustering within families
common, modest
which gene locus has been identified as a susceptibility locus from family studies of alzheimers
apolipoprotein E (APOE)
What was the result of the GWAS on Alzheimers disease
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)
what is apolipoprotein E
mediates transfer of cholesterol and phospholipids between cells and is important for injury repair in the brain
how are the variants of APOE different
E2 = protective
E2 -> E3 = Cys->Arg at 158
E3 -> E4 = Cys ->Arg at 112
what is the differece between APOE2 and APOE4
2 = lower chloesterol and higher APOE protein compared to 4
why is APOE4 a risk factor for alzheimers
due to the facilitating accumulation of b-amyloid protein in the brain
people who are APOE4 homozygoous are almost certain to develop Alzheimers by what age
80
the overall contribution of the APOIE locus to alzheimers susceptibility is approximately what ?
50%
what was the result when APOE was genotyped to predict the clinical response to tacrine
acrine – an acetylcholinesterase inhibitor
APOE4 carriers are less responsive to therapeutic acetylcholine inhibition
how to treat APOE4 driven Alzheimers
- Rationale for gene therapy is to increase the expression of the protective APOE2 variant to overcome the effects of APOE4
- issue with homozygous
What was the results of the twin studies and smoking
- 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
True or False - smoking is mongenic
False - it polygenic (as is addiction)
however there is also cultural factors that contribute
which CYP has been linked to smoking
- CYP2A6
- it is responsible for 90% of nicotine metabolism to cotinine (active metabolite)
what are the 3 types variation of CYP2A6
Wildtype, Mutation and deletion of whole genes
How is nicotinic acetylcholine receptor linked to smoking behaviour
□ 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.
What was results of the GWAS study on smoking behaviour
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
what is the polymorphims is associated with nicotine dependence and lung cancer
D398N polymorphism in exon 5 of CHRA5(15q25)
what is the link between schizophrenia and lung cancer
Reverse causation - smokers are more likely to take up smoking to relieve anxiety.
what is licensed to assist with smoking cessation
Antidepressant bupropion - Genotype for CYP2B6 affects metabolism of this drug and overall response
