Genetic basis of multifactorial disease Flashcards
What are the environmental risk factors for developing heart disease and what are the genetic risk factors?
Genetic:
• Cholesterol
• Blood pressure
Environmental
• Diet
• Smoking
• Exercise
What is meant by deterministic?
Single gene disorder
What is meant by Probablistic?
A complex trait, even if an individual has all of the susceptibility alleles, disease still depends on environmental aspects
What is meant by the continuum of genetic risk?
Some people will only have a couple of susceptibility alleles that increase the risk, others will have all of them
What is the liability threshold model?
- All the factors which influence the development of a multifactorial trait/disorder can be considered as a single entity: liability
- Liabilities of all individuals in a population form a continuous variable
- Individuals on the right of the line have the diagnosis of the disease- they have lots of genetic risk and some environmental risk
What is the threshold model?
- For a discontinuous phenotype with an underlying continuous distribution, a threshold exists above which the ‘abnormal’ phenotype is expressed.
- Population incidence is the proportion above this threshold in the general population
What is population incidence?
The proportion above the threshold in the general population
What is familial incidence?
The proportion among relatives above the threshold
Describe the susceptibility behind cleft palate
- Every embryo has a level of susceptibility
- The susceptibility is high or low and it follows a Gaussian distribution in the population
- If susceptibility exceeds the critical threshold, the embryo will start to develop cleft palate
- Susceptibility is the outcome of interaction of many genetic and environmental risk variants in utero
What is heritability of a disease?
The proportion of the total variance that is genetic
• Overall variance of the phenotype is the sum of the environmental and genetic variance
What does heritability provide information for?
The importance of genetic factors in the causation of disease
What is a mutation
A gene change which causes a genetic disorder
What is synonymous polymorphism?
Changes the DNA sequence, not the amino acid produced or the subsequent protein produced
What is non-synonymous missense polymorphism?
Changes the DNA sequence and the amino acid and therefore the protein coded for
What is a non-synonymous nonsense polymorphism?
Changes the DNA to code for a premature stop codon
What are the two definitions of a polymorphism?
- Any variation in the human genome that has a population frequency more than 1%
- Any variation in the human genome that does not cause a disease in its own right. It may however, predispose to a common disease i.e. is a risk factor
What is a major problem with family studies?
They don’t take into account the shared environment risk e.g. a poor diet, lifestyle choices
What is the difference to someone who is the relative of a female index case and someone who is the relative of a male index case?
- If you are related to a female index case, your risk as a first degree relative is higher than if it was a male index case.
- This is because more males get the disease so in order for a female to develop the condition, they must be to the far right of the curve and have many of the contributing genes
- Therefore if you are a relative of a female index case you are also more likely to have more of the contribution genes
What happens to the liability curve when talking about familial incidence?
The graph shifts to the right
What are the characteristics of multifactorial inheritance?
- Polygenic threshold characteristics tend to run in families because affected individuals have relatives that share their genes with them
- Parents who have several affected children are more likely to have more high risk alleles than parents who only have one affected children
- Recurrence risk increases with increasing numbers of previously affected children
What are monozygotic twins?
Twins that share all of their genes
What are dizygotic twins?
Twins that share 50% of their genes
What don’t twin studies take into account
That monozygotic twins may be more likely to be at risk of disease
What is an association study method?
- Affected group and a control group are genotyped
* Look at the polymorphism that you think affects the prevalence of the disease and compare the groups
What are the problems with the association study method?
- The disease may be influenced by 1 or 100 genes, how fo you know which to look at?
- How do you know which polymorphism to look at? There are 10-12million in the human genome
What are the options for significant association?
- May be true
- May be false and due to chance
- May be false and due to population stratification
What is it important to ensure about the control group in an association study?
The control group has to match your affected group otherwise true association may be due to ethnic differences between groups not disease
How can you find which gene or polymorphism may be responsible?
you can analyse the whole genome using a gene chip and analyse as many polymorphisms as you can and work out which is significant
What has a gene chip been used to find successfully?
A susceptibility locus for lung cancer
After identifying an association, what must then be looked at?
- Can the study be replicated in another population?
- How does the polymorphism affect the protein?
- Is there any clinical relevance
When will gene testing be useful when dealing with family history and when will it not be?
- Useful if it is caused by a single mutation inherited in a mendelian fashion but this is rare
- Not useful if it is due to a mix of genetic and environmental factors
When dealing with a family history of a common disease, what is the usual clinical management?
Conventional and targeted at treatable factors
What is associated with hypercholesterolaemia?
Apolipoprotein E
What are empirical risk estimates for producing heart disease based on?
- Cholesterol
- Blood pressure
- Diabetes
- Smoking
- Genetic tests have a limited role (LDL receptor mutations)
What should be done when a patient presents with a multifactorial condition?
- Exclude single gene/syndromic forms
- Think about recurrence risk (how many affected family members) calculated empirically unless there is a monogenic form of the disease
