Unit 5: Schizophrenia

This week, my Behavioral Genetics class focused on Schizophrenia as an example of how behavioral genetics explains a particular phenotype.  Here are the notes I would like to remember from this week.  Also, below this week's notes is a question I asked in (virtual) Office Hours and the professor's response:

Characteristics of Schizophrenia:

• Positive Symptoms (presence of something that is not normally there):  Thought disorder, delusions, hallucinations, movement disorder
• Negative symptoms (disruption in normal behaviors or emotional response):  Inappropriate affect, deterioration of social behavior, 
• Cognitive symptoms:  Impairments in working memory, attention, executive function
• Tends to start in late adolescence or early adulthood.

Epidemiology of Schizophrenia

• Males are at greater risk for all neurodevelopmental disorders, including schizophrenia.  
• Correlation with lower social classes (but not necessarily causation).
• Frequency of schizophrenia is similar across different countries and ethnic groups - but immigrants have higher rates of schizophrenia than non-immigrants.  
• Reduction in fertility

Twin Studies tell us about:  

1) Genetics of Schizophrenia

• Rare event to find twins (2% of population) with schizophrenia (1% of population).  
• Genetically identical twins are usually less than 50% concordant for schizophrenia - if one twin has it, it's (close to but) less than half the time that the identical twin also has it.
• They show that there is a genetic component, but that environmental factors also important.  
• Risk of schizophrenia increases exponentially with degree of genetic relatedness.  (Not just a linear increase, like in autosomal dominant diseases.)
• Exponential tells you that it must be multiple genes causing schizophrenia.  
• Seems to be between 60-80% heritable.  

2) Environmental Factors Related to Schizophrenia

• Shared environmental influence doesn't seem to be very important:  majority of schizophrenics do not have siblings with schizophrenia, being reared by an adoptive parent with schizophrenia does not increase risk of schizophrenia
• Non-Shared:  MZ concordance is around 50%.  Individuals with schizophrenia have larger ventricles.  Low birth weight, obstetrical complications, maternal conditions (such as malnutrition or flu).  

Identifying Schizophrenia Risk Alleles

1.  The Positional Cloning Strategy

- When you know a trait is heritable, find the position on the chromosome, then identify the genes on the chromosome.  This works well for traits that are caused by a single gene, but not so well for traits that are caused by multiple genes.  

-Candidate gene studies:  target specific genomic regions when looking for association.

-Leading study on this came up with no significant findings.  

2. The GWAS (Genome Wide Association Stragegy)

- The association between each SNP and the phenotype is tested using an array.  

- Learn that the effect of any specific variant is small, even if a trait is mostly heritable.

- Identified risk alleles tend to be very common (many of us are carrying some of them, but just not enough to express the phenotype of schizophrenia) - individually, they have small effects - but they implicate certain pathways.

- They have only figured out about 5% of the heritability of schizophrenia.
- This type of study misses rare variants and structural variants such as CNVs

3. Rare Variants and CNVs

- Rare variants:  There are certain disorders that are more likely when father is older.  With age, men produce more mutations in their gametes than women.
- 22.Q.11.2 syndrome given as example of CNV - individuals with this deletion have 20-30% likelihood of having schizophrenia, and 1% of people with schizophrenia have this deletion.
 -Note:  "De novo" means that neither the father nor the mother has the deletion, but somehow in cell reproduction, the child gets part of one of their two chromosomes cut out.  

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Here's the answer to my office hours question from last week:  Why is it that children with the same genetic deletion can have very different phenotypes?  (So for example, in 4q, many but not all kids have heart problems, Pierre Robin Sequence, finger and toe anomalies, etc.  Why wouldn't it be all or none if they have the same set of missing genes?)

1.  It's not always the same exact region that's being deleted - even if you have a matching number on the micro-array, these copy number variants cover millions of bases - so the deletions have significant overlap, but they are not actually exactly the same and there may be significant differences happening at the boundaries.  

2.  If you only have one whole copy of a particular chromosome (and the other contains a deletion), then the allele you have on the copy without the deletion becomes really important.  It gives an opportunity for recessive alleles to be expressed, when they would often be "overruled" by the matching dominant allele.  

3.  Genes at other regions of your genome can be interacting or impacting expression.