Genetics of Schizophrenia Flashcards
Symptoms of schizophrenia
POSITIVE SYMPTOMS
- delusions
- hallucinations
- “voices”
- disorganised speech
NEGATIVE SYMPTOMS
- social withdrawal
- apathy
- emotional blunting
COGNITIVE PROBLEMS
- memory
- attention
- processing speed
Prevalence of schizophrenia?
1% of population M + F
Age of onset of schizophrenia?
Late adolescence/early adulthood
List factors that can contribute to schizophrenia development
- genetics]- biggest factor
- paternal age
- maternal famine/infection
- hypoxia during birth
- birth season
- urban dwelling
- migration
- cannabis use
Evidence suggesting genetic role in schizophrenia development?
Monozygotic twins have a 48% risk of developing it
Dizygotic at 14% risk
(close blood relations have elevated risk)
Outcomes of first GWAS for schizophrenia?
Linked to multiple loci on different chromosomes
Candidate genes examples in schizophrenia?
- DA-receptor D2 treatments appear to be effective
- >1000 candidate genes were found though
How to map genetics of schizophrenia?
Common DNA variants- found by GWAS
Rare DNA variants:
- select families e.g. DISC1
- large scale CNV analysis
- exome sequencing
Features of the loci mapped by GWAS for schizophrenia?
- 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
Main findings of GWAS on schizophrenia?
- 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)
List the “rare” schizophrenia alleles and their outcome
- DISC1: gene affected by translocation -> forms of mental illness in some carriers
- 22q11: deletion -> mental illness in some carriers
What is velo-cardio-facial syndrome (VCFS)?
22q11 deletion
- hypoparathyroidism
- underdeveloped/absent thymus -> immune problems
- heart defects
- cleft lip/palate
Relationship between VCFS and schizophrenia?
- 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
Rare schizophrenia copy number variants (CNVs)
Chromosome 1, 15, 16
NRXN1
Linked to autism, epilepsy and mental retardation
Features of rare schizophrenia-associated loci?
- Highly, but not completely penetrant
- Not specific to schizophrenia
Importance of using De Novo variants to map schizophrenia?
[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
How to use De Novo variants to map schizophrenia?
- 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
Outcomes of large exome sequencing studies?
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
Outcome of combining GWAS and rare sequencing variants?
- synaptic pathway implicated in schizophrenia
- these pathways are also implicated in large scale studies of autism and epilepsy
Outcome of gene expression profiling?
Genes that are linked to the synaptome:
- SLC30A3
Pathways implicated in schizophrenia?
BA10 predominant pathways
BA22 predominant pathways
Shared pathways
Examples of shared pathways (BA10 and BA22) in schizophrenia?
Involved in:
- tissue remodelling
- calcium signalling
- cytoskeletal remodelling
- sex hormone signalling
- inflammatory response
- cell differentiation
BA10 pathways; physiology and pathophysiology
Physiological:
- protein folding
- amyloid proces?
Pathophysiological
Negative symptoms: cognitive and social dysfunction
BA22 pathways; physiology and pathophysiology
Physiological
- cell adhesion/ synaptic contact
- neurogenesis/axon guidance
- apoptosis
- autophagy
Pathophysiology
Positive symptoms: e.g. auditory hallucinations
Relevance of zinc transporter in schizophrenia?
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
