The Genetic Basis of Multifactorial Disease

Question 1

Identify genetic and environmental contributions to cystic fibrosis. Which of the two has more of an influence ?

Answer 1

Genetic factors: Known mutations in CF gene
Environmental factors: Treatment

Genetic factors have most of the influence

Question 2

Identify genetic and environmental contributions to angina/MI.

Answer 2

Genetic factors: Cholesterol Handling, Blood pressure
Environmental factors: Diet, Smoking, Exercise

Both have equal influence

Question 3

Identify genetic and environmental contributions to fracture.

Answer 3

Genetic factors: Bone density, Balance, Weight
Environmental factors: Diet, Ice on path, Age

Environmental factors have most of the influence

Question 4

Define Quantitative inheritance.

Answer 4

Combined result when many factors (including multiple genes and multiple environmental factors) combine to result in continuous traits and complex disorders.

Question 5

Define biological determinisim in the context of disease;

Answer 5

Single gene disorders = deterministic

Question 6

Define probabilism in the context of disease.

Answer 6

Complex traits = probabilistic- even if have all susceptibility alleles, disease still depends on whether encounter certain environmental hazards

Question 7

Define continuum of genetic risk.

Answer 7

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

Question 8

Describe the liability threshold model.

Answer 8

• 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
• The susceptibility is high or low and follows a Gaussian (normal) distribution in the general population
• Individuals on the right side of the line represent those with the disorder
• For a discontinuous phenotype ( i.e. affected vs non affected) with an underlying continuous distribution, a threshold exists above which the ‘abnormal’ phenotype is expressed. Population incidence is the proportion beyond the threshold in the general population. Among relatives, the proportion beyond the threshold is the familial incidence

Question 9

Explain how the liability model would apply to cleft palate in children.

Answer 9

• Every embryo has a certain susceptibility to cleft palate
• The susceptibility is high or low and follows a Gaussian distribution in the general population
• If the susceptibility exceeds a critical threshold, the embryo will develop cleft palate
• Susceptibility is the outcome of interaction of many genetic and environmental risk variants in utero

Question 10

Define heritability of a trait or disease. Why is it clinically important ?

Answer 10

Proportion of the total variance (sum of the environmental and genetic variance) that is genetic.
Important because it provides information of the importance of genetic factors in the causation of the disease.

Question 11

Define mutation.

Answer 11

A gene change that causes a genetic disorder (a disease causing mutation)

Question 12

Define polymorphism.

Answer 12

• Any variation in the human genome that has a population frequency of greater than 1%
or
• Any variation in the human genome that does not cause a disease in its own right. It may however, predispose to a common disease. ie is a risk factor
May be neutral or affect gene function

Question 13

Identify the techniques used to show that a disease has a genetic component.

Answer 13

1. Family studies

2. Twin studies

Question 14

Describe family studies.

Describe the liability curve for families.

Answer 14

• Identify the degree of risk of relatives developing disorders that other family members suffer (Answer the question, is it more common in relatives of those who are affected ?)
• This method does not take into account a risk caused by a shared environment such as a familial predilection for hamburgers in siblings
• For a disease with a genetic contribution you would expect a higher risk for family of affected people than the general population

-The curve for relatives of affected will be shifted to the right; so the familial incidence is higher than the general population incidence

Question 15

Describe the liability of groups with different disease incidence, using an example of groups.

Answer 15

E.g. condition where males are more prone to get the condition than females (i.e. have a lower incidence threshold)

• For a female to be affected, she must be at the high end of the curve (have more contributing genes)
• Therefore, the children or siblings of an affected female are more at risk of having a condition than if she was a he

Question 16

Describe the characteristics of multifactorial inheritance.

Answer 16

• Polygenic threshold characters tend to run in families because affected individuals have relatives who share their genes with them.
• Parents who have several affected children will have more high risk alleles than parents with only one affected child.
• Thus recurrence risk increases with increasing number of previously affected children

Question 17

Define a polygene.

Answer 17

Gene whose individual effect on a phenotype is too small to be observed, but which can act together with others to produce observable variation.

Question 18

Describe twin studies.

Answer 18

-Monozygotic twins share all their genes
-Dizygotic twins share on average 50% of their genes
-For a disease with a genetic contribution you would expect a monozygotic twin to be affected more frequently than a dizygotic twin
This doesn’t take into account the possibility that being a monozygotic twin itself predisposes to disease.

Question 19

Identify a way to determine whether a polymorphism contributes to a disease ?

Answer 19

Association study method= Analyze as many polymorphisms as you can across the genome in a disease population and a control group.
Work out which ones are significant (to find genetic variations associated with a particular disease).

Question 20

Describe the limitations of the association study method.

Answer 20

• How do you know which gene to look at ?
Disease may be influenced by 1 or 1000 genes
• How do you know which polymorphism to look at ?
10-12 million in human genome
• Significant association may be true BUT
Significant association may also be false and due to chance ALSO
Significant association may be false due to population stratification -control group has to match your affected
group otherwise apparent true associations may be due to ethnic genetic differences between groups, not disease.

Question 21

What are the questions to be answered after determining the association between a polymorphism and disease in an association study ?

Answer 21

1. Can the study be replicated in another population ?
2. How does the polymorphism affect the protein ?
3. Is there any clinical relevance ?

Question 22

Identify the main points to keep in mind when dealing with a family history of common disease in clinical practice.

Answer 22

1. Family history may suggest an inherited predispositon
   •More affected members
   •People affected at a younger age
2. Family history may be caused by a single mutation inherited in a mendelian fashion, but this is rare. If so , gene testing may help
3. Family history more likely to be caused by a mixture of genetic (risk polymorphisms) and environmental factors (multifactorial). Gene testing rarely helps.
4. For multifactorial conditions:
   •Exclude single gene / syndromic forms (rare)
   •Higher recurrence risk if
   -more affected family members
   -more severely affected family members
   •Risk or recurrence data is calculated empirically - gene tests rarely help unless there is a monogenic form of disease
5. Clinical management is usually conventional, targeted at treatable factors (environmental often)