Lecture 5: Genetics Flashcards
_________ is individual genetic make-up whilst ______ are physical and behavioural characteristics
Genotype – individual genetic make-up
Phenotype – physical and behavioural characteristics
Genetic epidemiology looks at whether there is evidence for _______________
heritability of a disorder
- If so, it looks at whether it appears to be a single gene or multiple genes?
What is the difference between Molecular genetics and molecular biology ?
Molecular genetics looks at whether the disorder is associated with specific genes and whether the disorder can be liked to gene variations.
Molecular biology, on the hand, looks at a candidate gene and what it does.
What have we learned from Family studies?
- Risk is never as large as the genetic relatedness
- First degree relatives have a greater risk than the population
- MZ twins and children of two parents with SZ have the highest risk (about %50)
- Siblings have lower risk than DZ twins
- Parents have lower risk than children or siblings
Therefore, Risk not as great as _____________
genetic relatedness
What is meant by MZ twins not 100% concordant?
Genes are not enough, there’s environmental (pre- and post-natal factors)
DZ twins at higher risk than __________
siblings
What does DZ twins at higher risk than siblings mean?
Shared pre-natal environment is important
But not enough
Parents at lower risk than __________
children
Why would Parents be at lower risk than children?
Parents environment may have been different
ie, may not have had a parent with SZ
More stable family, higher SES, etc
How do we examine the relative contributions of genetic vs environmental factors?
Through adoption studies
What did the adoption studies of children with SZ mothers reveal?
Children of SZ mothers more likely to develop SZ
Twins reared apart have similar risk
But, children of SZ mothers adopted into __________ also show higher risk of developing SZ or SZ-spectrum disorders
low-functioning families
SZ is genetically _______, but not genetically ________
SZ is genetically mediated, but not genetically determined
A Meta-analysis showed that _____ of risk genetically determined; _____ environmentally determined
Meta-analysis: 81% of risk genetically determined; 11% environmentally determined
Relatives of people with SZ are also______ more likely to have schizotypal or paranoid personality disorder
4-5 times
Relatives of people with SZ also have a higher risk of ________
other SZ-spectrum disorders
Relatives of people with SZ do not have greater risk for _________
affective disorder, anxiety disorders or alcoholism
There may be a link between SZ and which other disorder?
Bipolar disorder
Which is Consistent with _______ conferring risk for psychotic disorders
multiple genes
In the study of transmission of genetic risk, transmission models predict ____________________
what we should see and then match it to the evidence
In the case of SZ, what type of model does not fit?
A model of simple transmission of a single gene (or locus) does not fit
In the multiple gene models of SZ, multiple genes contribute to a __________, _______, ________ to develop SZ
liability, susceptibility or predisposition
If there are multiple genes and inheritance is not simple, then genes are likely to be common _____________________
in the general population
The _______ model predicts that many genes contribute to risk, but no one gene or genes is necessary
polygenetic
The _____________ model proposes that risk is a continuum including genetic and environmental factors
multifactorial threshold
In the multifactorial threshold model, the presence of _____________________ adds to risk
each gene or environmental factor
Which model proposes that genetic risk factors interact?
The gene interaction model
The gene interaction model proposes that genetic risk factors interact. This is more consistent with _____________
fall-off rate of risk in relatives
Both ________ and ____________ likely contribute
Both additive risk and gene interactions likely contribute
Environmental factors are also critical. Give an example.
Prenatal stressors: maternal stress and starvation
What did the Studies of the rate of SZ following famine in Netherlands show?
- twice likely to develop SZ (environmental risk factor was famine)
***Children estimated to have been conceived during 1944-45 were twice as likely to develop SZ (But, only 25 cases!)
What were the findings of the Anhui province study [ Rate of SZ following famine in China (1959-61)]?
- Twice likely to develop SZ (environmental factor was famine)
Children born in 1960 and 1961 were twice as likely to develop SZ (large number of cases)
What is the difference between linkage and association?
Linkage examines the whole genome looking for a relationship between a location and the disorder
Association tries to identify the relationship between one gene and the disorder
Moreover, Association Identifies a “candidate” gene based on relationship to one aspect of the phenotype
(e.g, A gene involved in dopamine regulation, brain region)
What are the difficulties in conducting linkage?
- Need multiple generations of the same family
- Hard to replicate
Which one is the most powerful technique, linkage or association?
Association - More specific, powerful technique
Linkage takes advantage of ___________________
naturally occurring gene recombination
Genes that recombine frequently are ____________
further apart
Genes that recombine frequently are further apart. Which means what?
- Either on the same or different chromosomes
- Greater distance creates more chances for recombination
Genes that recombine ________ are closer together or “linked”
less frequently
With the recombination frequency of many genes, we can estimate ____________________________
how far apart they are and their relative locations
Fewer generations make linkage studies _________
more difficult.
What is another limitation of linkage studies?
You need large numbers of well-characterized families, which is not easy.
The results of linkage studies to date are ________ and ________
not very conclusive and hard to replicate
What happens once a location is identified? candidate genes known to be close to that location can be studied using _________________
association studies.
There is evidence for linkage to ____________ and _________
several chromosomes and locations
In regard to association, what does it mean to test whether affected people are more likely to have a certain gene or gene variant?
To find a candidate gene
When associations look at individuals as opposed to families. Which specific question are they trying to answer?
Is a specific candidate gene more common in those with SZ compared to those without?
Most candidate genes related to the ____________ systems
dopamine, serotonin and GABA
Associations are limited by ____________
what we know about the pathophysiology of SZ
What does GWAS stand for?
Genome-wide association studies
GWAS Compare SZ and controls across the ________
entire genome
In GWAS studies, how many gene locations can be assed at the same time? And what are they testing for?
Millions of gene locations can be assessed at the same time
Tests the inheritance of allele (gene) variants
To control multiple comparisons, you need ______
very large samples
What were the main findings of the Multi-center study (2009)? How many potential location did they find? On which chromosomes?
How many genes may contribute to the risk?
Similar genes also contribute to which disorders?
- Found four potential locations (2 on chromosome 6)
- Also found that thousands of genes may contribute to risk
- Further, similar genes also contribute to risk for bipolar disorder and schizotypal personality disorder
The Multi-sample GWAS Schizophrenia Working Group (2014) found _______ significant gene locations
108
The Multi-sample GWAS Schizophrenia Working Group (2014) also found that these genes were expressed in which parts of the brain?
- Frontal (working memory, planning, attention)
- Angular gyrus (language)
- Inferior temporal (complex visual, faces, memory)
What was the key receptor in relation to SZ?
Dopamine D2 receptor
What were the key immune response associated with SZ?
CD 19 and 20
Name the three organs where these genes were less expressed (less relevant)
-Kidney, liver, muscles
What can we conclude from GWAS studies
That there are many genes expressed in various locations but we don’t know if these are a cause or a consequence of SZ.
However, what is one finding that is relevant from GWAS studies?
Greater risk with greater number of risk genes present
Discussed the overview of results in GWAS studies.
- The results of GWAS studies have _______________
- Each gene contributes _________________
- Supports the idea that _________________
- not always reproduced the results of candidate gene studies
- only a small effect
- a large number of common genes with small effects contribute to the disorder
What is meant by “a large number of common genes with small effects contribute to the disorder”?
- Each common gene might account for_____ of the risk
- Together, they would only account for ____ of the total risk
- Each common gene might account for 1-2% of the risk
- Together, they would only account for 25-50% of the total risk
What is the Common disease, rare variants hypothesis? (hint: what is the difference between common and rare genes in terms of effect?)
- Many common gene variants of small effect
- Rare gene variants of large effect
(which can cause SZ)
Further, 2009 study found that similar genes are associated with both SZ and _____ supports the idea of ______
- Bipolar
- common gene spectrum
What is a limitation of family studies?
Family studies assume that environment is constant and that genes and environment do not interact
(we know that this is not the case)
What are other limitations of these types of studies we covered in this lecture?
- SZ symptoms are _____________
- No ________ at the individual level
- Genetic studies are only as good as________
- SZ and other disorders part of _____________
- Overlap in risk with other disorders means ______
- variable and sub-types (e.g., positive/negative symptoms) not clear
- diagnostic bio-marker
- as our diagnostic criteria
- a spectrum with shared risk.
- results are not specific
We can conclude that SZ is genetically _______, but not genetically _______
SZ is genetically influenced, but not genetically determined
___________ genes are involved.
The specific genes likely vary between ________ and _____________
- Multiple
- individuals
- families
Part of the genetic risk is accounted for by ______ variants that are _____ risk individually
- common
- low
There also an accounted for ________
rare, high-risk variants
Risk is likely ______________________
Risk is likely additive (more risk genes = greater risk)
SZ genes are also likely to interact with ___________
each other and/or with environmental risk factors
Similar genes may be related to risk for other psychotic disorders, especially __________________
SZ spectrum and bipolar