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Neuroscience and Mental Health > Genetics of Schizophrenia > Flashcards

Genetics of Schizophrenia Flashcards

1
Q

Symptoms of schizophrenia

A

POSITIVE SYMPTOMS

  • delusions
  • hallucinations
  • “voices”
  • disorganised speech

NEGATIVE SYMPTOMS

  • social withdrawal
  • apathy
  • emotional blunting

COGNITIVE PROBLEMS

  • memory
  • attention
  • processing speed
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2
Q

Prevalence of schizophrenia?

A

1% of population M + F

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3
Q

Age of onset of schizophrenia?

A

Late adolescence/early adulthood

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4
Q

List factors that can contribute to schizophrenia development

A
  • genetics]- biggest factor
  • paternal age
  • maternal famine/infection
  • hypoxia during birth
  • birth season
  • urban dwelling
  • migration
  • cannabis use
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5
Q

Evidence suggesting genetic role in schizophrenia development?

A

Monozygotic twins have a 48% risk of developing it

Dizygotic at 14% risk

(close blood relations have elevated risk)

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6
Q

Outcomes of first GWAS for schizophrenia?

A

Linked to multiple loci on different chromosomes

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7
Q

Candidate genes examples in schizophrenia?

A
  • DA-receptor D2 treatments appear to be effective

- >1000 candidate genes were found though

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8
Q

How to map genetics of schizophrenia?

A

Common DNA variants- found by GWAS

Rare DNA variants:

  • select families e.g. DISC1
  • large scale CNV analysis
  • exome sequencing
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9
Q

Features of the loci mapped by GWAS for schizophrenia?

A
  • 75% are protein coding related
  • notable association with D2 DA-receptor
  • main association w/ genes for glutamate neurotransmission and syn plasticity: GRM3, GRIN2A, GRIA1, SRR
  • VGCC subunits: CACNA1I, CACNA1C, CACNB2
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10
Q

Main findings of GWAS on schizophrenia?

A
  • 8300 common SNPs contribute
  • hits converge on genes in brain and immune tissues
  • MHC locus has strongest association
  • genes involved in glutamate signalling
  • DRD2 (DA-r D2)
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11
Q

List the “rare” schizophrenia alleles and their outcome

A
  • DISC1: gene affected by translocation -> forms of mental illness in some carriers
  • 22q11: deletion -> mental illness in some carriers
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12
Q

What is velo-cardio-facial syndrome (VCFS)?

A

22q11 deletion

  • hypoparathyroidism
  • underdeveloped/absent thymus -> immune problems
  • heart defects
  • cleft lip/palate
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13
Q

Relationship between VCFS and schizophrenia?

A
  • up to 1/3 of VCFS pts may develop schizophrenia or another psych illness
  • 1% of schizophrenia pts have 22qDS (VCFS)
  • The schizophrenia in VCFS is indistinguishable by symptoms, treatment response, neurocog. profile or MRI brain anomalies
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14
Q

Rare schizophrenia copy number variants (CNVs)

A

Chromosome 1, 15, 16
NRXN1

Linked to autism, epilepsy and mental retardation

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15
Q

Features of rare schizophrenia-associated loci?

A
  • Highly, but not completely penetrant

- Not specific to schizophrenia

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16
Q

Importance of using De Novo variants to map schizophrenia?

A

[present in child but neither parent]

  • rare enough (0-3 per exome) for us to identify causal variants
  • very successful approach to identifying the cause of Mendelian diseases through sequencing
17
Q

How to use De Novo variants to map schizophrenia?

A
  • examine “sporadic” cases]- difficult to find though
  • compare frequency of de novos in cases vs controls
  • make assumptions about causality for those present in cases
18
Q

Outcomes of large exome sequencing studies?

A

Fromer et al

  • no evidence for increased rates of de novo mutations in schizo cases
  • some genes need more than one “hit”
  • enrichment of mutations of genes in ARC, NMDAR and FMRP pathways

Purcell et al

  • id’d no risk alleles
  • no risk genes
  • enrichment of mutation in genes for ARC, NMDAR, FMRP and calcium signalling pathways
19
Q

Outcome of combining GWAS and rare sequencing variants?

A
  • synaptic pathway implicated in schizophrenia

- these pathways are also implicated in large scale studies of autism and epilepsy

20
Q

Outcome of gene expression profiling?

A

Genes that are linked to the synaptome:

  • SLC30A3
21
Q

Pathways implicated in schizophrenia?

A

BA10 predominant pathways

BA22 predominant pathways

Shared pathways

22
Q

Examples of shared pathways (BA10 and BA22) in schizophrenia?

A

Involved in:

  • tissue remodelling
  • calcium signalling
  • cytoskeletal remodelling
  • sex hormone signalling
  • inflammatory response
  • cell differentiation
23
Q

BA10 pathways; physiology and pathophysiology

A

Physiological:

  • protein folding
  • amyloid proces?

Pathophysiological
Negative symptoms: cognitive and social dysfunction

24
Q

BA22 pathways; physiology and pathophysiology

A

Physiological

  • cell adhesion/ synaptic contact
  • neurogenesis/axon guidance
  • apoptosis
  • autophagy

Pathophysiology
Positive symptoms: e.g. auditory hallucinations

25
Q

Relevance of zinc transporter in schizophrenia?

A

ZNT3 = SLC30A3

  • significantly decreased in schizophrenia: impact on synaptic transmission
  • brain specific- present in SV sub-populations
  • suboptimal Zn nutrition during rat gestation -> long term effects on brain function
  • Zn supplementation beneficial in unipolar depression

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