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Neuroscience > Lecture 9 - Generics of Schiz > Flashcards

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

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2
Q

What are vase pairs in typical genetics

A

Differ along strand DNA

Adenine-Thymine A-T

Guanine-Cytosine G-C

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3
Q

Heritability of Schiz

A

81%

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4
Q

Heritability bipolar

A

85%

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5
Q

Heritability Alzheimer’s Disease

A

75%

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6
Q

Heritability Autism

A

80%

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7
Q

Heritability anxiety

A

28%

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8
Q

What does heritability mean

A

Proportion of total variation between individuals in given population due to genetic variation

Not inheritance

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9
Q

What can go wrong with genes

A

Difference in codes affects phenotypes = expression

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10
Q

What can go wrong with genes SNP

A

SNP = altercations code but doesn’t change meaning

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11
Q

What can go wrong with genes mutation

A

Mutation = completely changes meaning, decrease making enzyme controls

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12
Q

What can go wrong with genes duplication

A

Duplication = copy number variation, harder, impossible read alter function

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13
Q

What can go wrong with genes deletion

A

Deletion = make harder/impossible read

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14
Q

What is the percentage likelihood Schiz in general population

A

1%

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15
Q

What is the percentage likelihood Schiz in identical twins

A

48%

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16
Q

What is the percentage likelihood Schiz in fraternal twins

A

17%

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17
Q

What is the percentage likelihood Schiz in children

A

13%

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18
Q

What is the percentage likelihood Schiz in siblings

A

9

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19
Q

What is the percentage likelihood Schiz in parents

A

6

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20
Q

What is the percentage likelihood Schiz in first cousins uncles/aunts

A

2

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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
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22
Q

Outline family studies of Schiz

A

Begin 1916 first systematic studies

“Feeble mindedness” ran in families

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23
Q

Outline limitations of family studies

A

No control groups

Environments are similar between family members

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24
Q

Outline Maudsley Twin Study of Schiz

A

Individuals registered for treatment at Maudsley hospital 1948-93

106 interviews

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25
Q

Outline results in Maudsley Twin Study of Schiz

A

Correlation psychiatric disorders in MZ twins .81

DZ twins .31

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26
Q

Outline Finnish Twin Study of Schiz

A

Centralised hospital records 1969-91
Similar to Maudsley study
508 records

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27
Q

Outline Finnish Twin Study of Schiz results

A

Showed correlation in
MZ twins .84
DZ twins .34

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28
Q

Limitations of twin studies

A

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

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29
Q

Outline Adoption study of Oregon Study

A

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

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30
Q

Outline adoption study of Danish Studies

A

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

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31
Q

Limitations of adoption studies

A

Adoptive parents often matched so very similar environments

Adoptive parents not representative population - higher SES, lower drug and alcohol use

32
Q

Outline what a Genome Wide Association Study is

A

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
Q

What is an SNP

A

Single nucleotide polymorphism a single nucleotide
A C T G
Alteration in genetic code

34
Q

What is a limitation of Genome Wide Association Studies

A

Large samples 20,000+ cases for statistical validity

35
Q

What is the biological insight from 108 Schiz associated genetic loci

A

36,000 sample
GWAS Approach
Highly significant identification genetic mock
108 loci found including coding D2 receptors, glutamate receptors and immune system

36
Q

Do association studies have to be the same family

A

No can

Investigate few candidate genes based specific hypothesis

Investigate whole genome using thousands marker loci

37
Q

Outline landmark 2014 GWAS

A

Identified 108 different loci

Identification gene not mean causation - experiments show role

38
Q

Outline key pathways converge SNPs and CNVs in different populations

A

Glutamate signalling

Immune function

Dopamine signalling

Synaptic plasticity

39
Q

Outline Velo-Cardiofacial Syndrome and Schiz

A

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
Q

What are the symptoms of cell cardio facial syndrome

A

Cleft palate
Heart defects
Distinctive facial features
- elongated face, almond shaped eyes, long wide nose. Dark red rings under eyes, open mouthed expression

41
Q

Outline considerations when finding associations between genes with Schiz

A

Just because gene not identified doesn’t mean not important

Just because gene identified doesn’t mean it is important

42
Q

Outline Dysbindin hypothesised role

A

Via synaptic glutamate release

43
Q

Outline Neuregulin hypothesised role

A

Multiple including effects synaptic plasticity neuro development and transmitter activity

44
Q

Outline COMT hypothesised role

A

Metabolises cerebral monoamines including dopamine

45
Q

Outline disrupted in Schiz DISC1 hypothesised role

A

Poorly understood possible roles suggested in synaptogenesis and neurodevelopment

46
Q

Outline Metabotropic Glutamate Receptor hypothesised role

A

NMDA receptor effects via affecting

47
Q

Outline Proline Dehydrogenase hypothesised role

A

Modulation of synaptic transmission

48
Q

Outline D-amino acid oxidase activator DAOA also known G72 hypothesised role

A

Possibly affects ratio L to D serine ratio which may have role in regulation of NMDA receptor

49
Q

What is the Two Hit Hypothesis

A 
Genetics = hit 1
Environments = hit 2

Environment be prenatal, postnatal, immune challenge, adverse social environment, drugs

50
Q

What is the development cascade towards Schiz

A

Subtle motor, cognitive, social deficits ->
Social anxiety, quasi psychotic ideas, depression ->
Dopamine dysregulation ->
Psychosis

51
Q

What contributes to dopamine dysregulation

A

Drug abuse e.g. cannabis

NTs: COMT

52
Q

Minor head physical abnormalities associated Schiz

A

2 or more hair whorls

Head circumference outside normal range

53
Q

Minor eyes physical abnormalities associated Schiz

A

Shin fold inner corner eye

Wide set eyes

54
Q

Minor ears physical abnormalities associated Schiz

A

Low set ears

Asymmetrical

55
Q

Minor mouth physical abnormalities associated Schiz

A

High steepled palate

Furrowed tongue

56
Q

Minor hands physical abnormalities associated Schiz

A

Curves fifth finger

Single transverse crease in palm

57
Q

Minor feet physical abnormalities associated Schiz

A

3rd toe longer than 2nd

Partial webbing 2 middle toes

58
Q

Outline abnormal eye movements in Schiz - Kety et al 2002

A

Smooth pursuit eye movement tracings
Follow target moved sinusoidally
Recorded infrared reflectometry

59
Q

Outline abnormal eye movements in Schiz - Kety et al 2002 results and conclusions

A

Tracing Schiz patient significantly more irregular

Suggesting low gain pursuit with frequent catch up saccadic eye movements

60
Q

Outline hippocampal cell changes in Schiz

A

Post mortem Studies
Cellular disarray hippocampus Schiz
Smaller less organised

61
Q

Limitation post mortem Studies

A

Issues taking medication long time

Effects result medication or disease

62
Q

Outline micro graphs pyramidal cells in cerebral cortex stained with Golgi method

A

Thicker
Smoother
Less density

63
Q

Outline seasonality affects of Schiz

A

Greater Schiz born Dec-March

Time lagged correlation with temperature. Schiz Influence by temperature 6 months previously

64
Q

Outline seasonality affects and temperature correlations of Schiz explanation

A

Temperature, vitamin D
Higher in summer,
Move from hot to cold countries higher incidence
Immunity

65
Q

Outline influenza and Schiz

A

Exposure glue epidemics 3-7th month gestation increases Schiz

First highlight potential role immune system

66
Q

Outline maternal malnutrition and Schiz

A

Increased births people Schiz following feminine

Chinese famine 1959-61

67
Q

Outline immune system and Schiz evidence

A

Genes involved immune responses shown GWAS studies
Prenatal maternal infection risk factor
Immune abnormalities in blood and CNS - white blood cells, cytokines

68
Q

Outline immune system evidence in animal models in Schiz

A

Inducing infection in pregnant mothers

Offspring show behavioural abnormalities and neurochemical abnormalities that are reversed by antipsychotic drugs

69
Q

What happens when in neurodevelopment

A

Amount synapses you have - effect neurotransmission
Taking drugs, adverse family environment
Lots key points along neurodevelopment trajectory make us vulnerable

70
Q

Outline Cytokines role

A

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
Q

Outline Cytokines role and Schiz

A

Mechanisms which maternal infection produces abnormal brain abnormality which increases risk Schiz

72
Q

Outline latent Inhibition and dopamine in off spring at 35 days

A

No effect latent Inhibition or stimulated dopamine release in striatum in off spring 35 days

73
Q

Outline latent Inhibition and dopamine in off spring at 90 days

A

Disrupted latent Inhibition

Enhanced stimulated dopamine

74
Q

How can disrupted latent Inhibition and enhanced dopamine be reversed

A

Antipsychotic haloperidol

75
Q

Outline POLY I:C Acid

A

Induced immune activation
Mimic viral exposure
Elicits immune responses similar those viral infection
Inducing release pro inflammatory cytokines

Neuroscience (12 decks)

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