Lecture 9 - Generics of Schiz Flashcards
1
Q
Outline genetics for the typical person
A
Nucleus cell 23 chromosome pairs
Chromosomes - set DNA
DNA series codes and bases code different molecules protein
Gene section codes for particular molecules
2
Q
What are vase pairs in typical genetics
A
Differ along strand DNA
Adenine-Thymine A-T
Guanine-Cytosine G-C
3
Q
Heritability of Schiz
A
81%
4
Q
Heritability bipolar
A
85%
5
Q
Heritability Alzheimer’s Disease
A
75%
6
Q
Heritability Autism
A
80%
7
Q
Heritability anxiety
A
28%
8
Q
What does heritability mean
A
Proportion of total variation between individuals in given population due to genetic variation
Not inheritance
9
Q
What can go wrong with genes
A
Difference in codes affects phenotypes = expression
10
Q
What can go wrong with genes SNP
A
SNP = altercations code but doesn’t change meaning
11
Q
What can go wrong with genes mutation
A
Mutation = completely changes meaning, decrease making enzyme controls
12
Q
What can go wrong with genes duplication
A
Duplication = copy number variation, harder, impossible read alter function
13
Q
What can go wrong with genes deletion
A
Deletion = make harder/impossible read
14
Q
What is the percentage likelihood Schiz in general population
A
1%
15
Q
What is the percentage likelihood Schiz in identical twins
A
48%
16
Q
What is the percentage likelihood Schiz in fraternal twins
A
17%
17
Q
What is the percentage likelihood Schiz in children
A
13%
18
Q
What is the percentage likelihood Schiz in siblings
A
9
19
Q
What is the percentage likelihood Schiz in parents
A
6
20
Q
What is the percentage likelihood Schiz in first cousins uncles/aunts
A
2
21
Q
What are the approaches to the study of genetics
A
Family studies Twin studies Adopted studies Linkage analysis studies Genome wide association studies GWAS
22
Q
Outline family studies of Schiz
A
Begin 1916 first systematic studies
“Feeble mindedness” ran in families
23
Q
Outline limitations of family studies
A
No control groups
Environments are similar between family members
24
Q
Outline Maudsley Twin Study of Schiz
A
Individuals registered for treatment at Maudsley hospital 1948-93
106 interviews
25
Outline results in Maudsley Twin Study of Schiz
Correlation psychiatric disorders in MZ twins .81
| DZ twins .31
26
Outline Finnish Twin Study of Schiz
Centralised hospital records 1969-91
Similar to Maudsley study
508 records
27
Outline Finnish Twin Study of Schiz results
Showed correlation in
MZ twins .84
DZ twins .34
28
Limitations of twin studies
Different approach have different impacts on findings
Can’t ask questions or clarify things
Is environment really constant between MZ and DZ?
Different treatment MZ (treatment more similar) and DZ
29
Outline Adoption study of Oregon Study
50 children born women with Schiz - adopted within 3 days of birth. Matched with adopted children parents with no record psychiatric admittance
10.6% rate Schiz - same rate people reared by parents with Schiz
30
Outline adoption study of Danish Studies
34 adoptees hospitalised Schiz
34 control
Rate Schiz first degree Biological relatives 7.9% compared 0.9% controls
Sharing genes but not environment 10x higher risk
Sharing environment but no genes no increased risk
31
Limitations of adoption studies
Adoptive parents often matched so very similar environments
Adoptive parents not representative population - higher SES, lower drug and alcohol use
32
Outline what a Genome Wide Association Study is
Find differences in frequencies of SNPs between populations - difference frequency genes and folding
Code all sequences genes for Schiz compare to control. Pick out differences
Asks whether frequency each SNP differs between patients and controls
33
What is an SNP
Single nucleotide polymorphism a single nucleotide
A C T G
Alteration in genetic code
34
What is a limitation of Genome Wide Association Studies
Large samples 20,000+ cases for statistical validity
35
What is the biological insight from 108 Schiz associated genetic loci
36,000 sample
GWAS Approach
Highly significant identification genetic mock
108 loci found including coding D2 receptors, glutamate receptors and immune system
36
Do association studies have to be the same family
No can
Investigate few candidate genes based specific hypothesis
Investigate whole genome using thousands marker loci
37
Outline landmark 2014 GWAS
Identified 108 different loci
| Identification gene not mean causation - experiments show role
38
Outline key pathways converge SNPs and CNVs in different populations
Glutamate signalling
Immune function
Dopamine signalling
Synaptic plasticity
39
Outline Velo-Cardiofacial Syndrome and Schiz
Look genetic differences in Syndrome with known genetic origins
VCFS genetic disorder missing part of chromosome 22q11 = CNV deletion
Prevalence Schiz 25x normal population
40
What are the symptoms of cell cardio facial syndrome
Cleft palate
Heart defects
Distinctive facial features
- elongated face, almond shaped eyes, long wide nose. Dark red rings under eyes, open mouthed expression
41
Outline considerations when finding associations between genes with Schiz
Just because gene not identified doesn’t mean not important
Just because gene identified doesn’t mean it is important
42
Outline Dysbindin hypothesised role
Via synaptic glutamate release
43
Outline Neuregulin hypothesised role
Multiple including effects synaptic plasticity neuro development and transmitter activity
44
Outline COMT hypothesised role
Metabolises cerebral monoamines including dopamine
45
Outline disrupted in Schiz DISC1 hypothesised role
Poorly understood possible roles suggested in synaptogenesis and neurodevelopment
46
Outline Metabotropic Glutamate Receptor hypothesised role
NMDA receptor effects via affecting
47
Outline Proline Dehydrogenase hypothesised role
Modulation of synaptic transmission
48
Outline D-amino acid oxidase activator DAOA also known G72 hypothesised role
Possibly affects ratio L to D serine ratio which may have role in regulation of NMDA receptor
49
What is the Two Hit Hypothesis
```
Genetics = hit 1
Environments = hit 2
```
Environment be prenatal, postnatal, immune challenge, adverse social environment, drugs
50
What is the development cascade towards Schiz
Subtle motor, cognitive, social deficits ->
Social anxiety, quasi psychotic ideas, depression ->
Dopamine dysregulation ->
Psychosis
51
What contributes to dopamine dysregulation
Drug abuse e.g. cannabis
| NTs: COMT
52
Minor head physical abnormalities associated Schiz
2 or more hair whorls
| Head circumference outside normal range
53
Minor eyes physical abnormalities associated Schiz
Shin fold inner corner eye
| Wide set eyes
54
Minor ears physical abnormalities associated Schiz
Low set ears
| Asymmetrical
55
Minor mouth physical abnormalities associated Schiz
High steepled palate
| Furrowed tongue
56
Minor hands physical abnormalities associated Schiz
Curves fifth finger
| Single transverse crease in palm
57
Minor feet physical abnormalities associated Schiz
3rd toe longer than 2nd
| Partial webbing 2 middle toes
58
Outline abnormal eye movements in Schiz - Kety et al 2002
Smooth pursuit eye movement tracings
Follow target moved sinusoidally
Recorded infrared reflectometry
59
Outline abnormal eye movements in Schiz - Kety et al 2002 results and conclusions
Tracing Schiz patient significantly more irregular
| Suggesting low gain pursuit with frequent catch up saccadic eye movements
60
Outline hippocampal cell changes in Schiz
Post mortem Studies
Cellular disarray hippocampus Schiz
Smaller less organised
61
Limitation post mortem Studies
Issues taking medication long time
Effects result medication or disease
62
Outline micro graphs pyramidal cells in cerebral cortex stained with Golgi method
Thicker
Smoother
Less density
63
Outline seasonality affects of Schiz
Greater Schiz born Dec-March
Time lagged correlation with temperature. Schiz Influence by temperature 6 months previously
64
Outline seasonality affects and temperature correlations of Schiz explanation
Temperature, vitamin D
Higher in summer,
Move from hot to cold countries higher incidence
Immunity
65
Outline influenza and Schiz
Exposure glue epidemics 3-7th month gestation increases Schiz
First highlight potential role immune system
66
Outline maternal malnutrition and Schiz
Increased births people Schiz following feminine
Chinese famine 1959-61
67
Outline immune system and Schiz evidence
Genes involved immune responses shown GWAS studies
Prenatal maternal infection risk factor
Immune abnormalities in blood and CNS - white blood cells, cytokines
68
Outline immune system evidence in animal models in Schiz
Inducing infection in pregnant mothers
| Offspring show behavioural abnormalities and neurochemical abnormalities that are reversed by antipsychotic drugs
69
What happens when in neurodevelopment
Amount synapses you have - effect neurotransmission
Taking drugs, adverse family environment
Lots key points along neurodevelopment trajectory make us vulnerable
70
Outline Cytokines role
Cytokines family soluble proteins role systemic mediators host response to infection
Involved inflammatory response non infectious agents and insults
Contributors normal development and function CNS
71
Outline Cytokines role and Schiz
Mechanisms which maternal infection produces abnormal brain abnormality which increases risk Schiz
72
Outline latent Inhibition and dopamine in off spring at 35 days
No effect latent Inhibition or stimulated dopamine release in striatum in off spring 35 days
73
Outline latent Inhibition and dopamine in off spring at 90 days
Disrupted latent Inhibition
| Enhanced stimulated dopamine
74
How can disrupted latent Inhibition and enhanced dopamine be reversed
Antipsychotic haloperidol
75
Outline POLY I:C Acid
Induced immune activation
Mimic viral exposure
Elicits immune responses similar those viral infection
Inducing release pro inflammatory cytokines
