Genetics of Schizophrenia

Question 1

When is the typical onset of schizophrenia?

Answer 1

Late adolescence or early adulthood

Question 2

State the 3 main symptom domains of schizophrenia

Answer 2

Positive symptoms, negative symptoms, cognitive problems

Question 3

State some positive symptoms of schizophrenia

Answer 3

Delusions, hallucinations, disorganised speech

Question 4

State some negative symptoms of schizophrenia

Answer 4

Social withdrawal, apathy, emotional blunting

Question 5

State some cognitive problems of schizophrenia

Answer 5

Difficulties with memory, attention, and processing speed

Question 6

Give at least 5 risk factors implicated in schizophrenia

Answer 6

Genetics, paternal age, maternal famine, infection while pregnant, season of birth, hypoxia at birth, urban dwelling, adolescent cannabis use, migration

Question 7

State the monozygotic twin concordance of schizophrenia

Answer 7

48%

Question 8

What is a linkage study?

Answer 8

A study looking at the co-inheritance of genetic markers on chromosomes in families with high incidence of a disease to try and identify markers linked to that disease

Question 9

Why are dopamine receptor D2 genes or associated genes candidate genes in schizophrenia?

Answer 9

Most drugs for schizophrenia target dopamine receptor D2

Question 10

What is the aim of genome wide association studies (GWAS)?

Answer 10

To identify single base variants (SNPs) associated with a clinical condition

Question 11

Which main gene areas have been implicated in schizophrenia by genome wide association studies?

Answer 11

Genes involved in glutamate neurotransmission, synaptic plasticity, and voltage-gated calcium channel subunits

Question 12

Where are most SNPs implicated in schizophrenia expressed?

Answer 12

The brain and immune tissues, particularly the MHC locus

Question 13

Name 2 rare schizophrenia alleles

Answer 13

Disrupted in schizophrenia 1 (DISC1) and 22q11 deletion syndrome

Question 14

Which mental disorders does disrupted in schizophrenia 1 (DISC1) predispose to?

Answer 14

Schizophrenia, bipolar disorder, recurrent major depression, adolescent conduct disorder, anxiety disorder, alcohol abuse

Question 15

What is disrupted in schizophrenia 1 (DISC1)?

Answer 15

A translocation between chromosome 1 and chromosome 11

Question 16

What does 22q11 deletion syndrome cause?

Answer 16

Velo-cardial facial syndrome, characterised by hypoparathyroidism, and underdeveloped or absent thymus (and consequent immune problems), heart defecrs, and a cleft lip or palate - as well as schizophrenia in 1/3 of patients

Question 17

What type of study identifies deletion syndromes?

Answer 17

Copy number variant studies

Question 18

Which disorders is 15q11 deletion associated with?

Answer 18

Autism spectrum disorder, Angelmann syndrome, Prader-Willi syndrome

Question 19

What is next generation sequencing used to identify?

Answer 19

De novo mutations - those found in the child but not either parent

Question 20

Describe the results of Fromer et al & Purcell et al’s 2014 studies into de novo mutations in schizophrenia

Answer 20

De novo mutations were not more common in schizophrenics, but mutations were more commonly located in the ARC, MNDAr, and FMRP pathways (synaptic pathways)

Question 21

What does transcriptomics look at?

Answer 21

All the genes present in and expressed by a tissue

Question 22

State the brain regions implicated in schizophrenia

Answer 22

Frontal and temporal cortices

Question 23

Name a candidate gene in schizophrenia identified from expression profiling studies

Answer 23

Zinc transporter ZnT3

Question 24

Describe the relationship between zinc and brain function

Answer 24

Suboptimal zinc nutrition during gestation in rats causes long-term effects on brain function (Aimo et al, 2010), and zinc supplementation is beneficial in major depression (Nowak et al, 2011)

Question 25

Describe the relationship between ZnT3 and schizophrenia

Answer 25

ZnT3 has been identified as a candidate gene in expression profiling, and there are four SNPs associated with ZnT3 and schizophrenia - all of which are consistent with a dominant model for disease penetrance

Question 26

Where do the candidate differentially expressed genes implicated in schizophrenia appear to localise to? (Maycox et al, 2009)

Answer 26

The synaptome