Genetic basis of multifactorial disease

Question 1

What are the environmental risk factors for developing heart disease and what are the genetic risk factors?

Answer 1

Genetic:
• Cholesterol
• Blood pressure

Environmental
• Diet
• Smoking
• Exercise

Question 2

What is meant by deterministic?

Answer 2

Single gene disorder

Question 3

What is meant by Probablistic?

Answer 3

A complex trait, even if an individual has all of the susceptibility alleles, disease still depends on environmental aspects

Question 4

What is meant by the continuum of genetic risk?

Answer 4

Some people will only have a couple of susceptibility alleles that increase the risk, others will have all of them

Question 5

What is the liability threshold model?

Answer 5

• 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

Question 6

What is the threshold model?

Answer 6

• 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

Question 7

What is population incidence?

Answer 7

The proportion above the threshold in the general population

Question 8

What is familial incidence?

Answer 8

The proportion among relatives above the threshold

Question 9

Describe the susceptibility behind cleft palate

Answer 9

• 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

Question 10

What is heritability of a disease?

Answer 10

The proportion of the total variance that is genetic

• Overall variance of the phenotype is the sum of the environmental and genetic variance

Question 11

What does heritability provide information for?

Answer 11

The importance of genetic factors in the causation of disease

Question 12

What is a mutation

Answer 12

A gene change which causes a genetic disorder

Question 13

What is synonymous polymorphism?

Answer 13

Changes the DNA sequence, not the amino acid produced or the subsequent protein produced

Question 14

What is non-synonymous missense polymorphism?

Answer 14

Changes the DNA sequence and the amino acid and therefore the protein coded for

Question 15

What is a non-synonymous nonsense polymorphism?

Answer 15

Changes the DNA to code for a premature stop codon

Question 16

What are the two definitions of a polymorphism?

Answer 16

• 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

Question 17

What is a major problem with family studies?

Answer 17

They don’t take into account the shared environment risk e.g. a poor diet, lifestyle choices

Question 18

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?

Answer 18

• 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

Question 19

What happens to the liability curve when talking about familial incidence?

Answer 19

The graph shifts to the right

Question 20

What are the characteristics of multifactorial inheritance?

Answer 20

• 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

Question 21

What are monozygotic twins?

Answer 21

Twins that share all of their genes

Question 22

What are dizygotic twins?

Answer 22

Twins that share 50% of their genes

Question 23

What don’t twin studies take into account

Answer 23

That monozygotic twins may be more likely to be at risk of disease

Question 24

What is an association study method?

Answer 24

• 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

Question 25

What are the problems with the association study method?

Answer 25

• 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

Question 26

What are the options for significant association?

Answer 26

• May be true
• May be false and due to chance
• May be false and due to population stratification

Question 27

What is it important to ensure about the control group in an association study?

Answer 27

The control group has to match your affected group otherwise true association may be due to ethnic differences between groups not disease

Question 28

How can you find which gene or polymorphism may be responsible?

Answer 28

you can analyse the whole genome using a gene chip and analyse as many polymorphisms as you can and work out which is significant

Question 29

What has a gene chip been used to find successfully?

Answer 29

A susceptibility locus for lung cancer

Question 30

After identifying an association, what must then be looked at?

Answer 30

• Can the study be replicated in another population?
• How does the polymorphism affect the protein?
• Is there any clinical relevance

Question 31

When will gene testing be useful when dealing with family history and when will it not be?

Answer 31

• 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

Question 32

When dealing with a family history of a common disease, what is the usual clinical management?

Answer 32

Conventional and targeted at treatable factors

Question 33

What is associated with hypercholesterolaemia?

Answer 33

Apolipoprotein E

Question 34

What are empirical risk estimates for producing heart disease based on?

Answer 34

• Cholesterol
• Blood pressure
• Diabetes
• Smoking
• Genetic tests have a limited role (LDL receptor mutations)

Question 35

What should be done when a patient presents with a multifactorial condition?

Answer 35

• 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