Genetic Basis of Multifactorial Disease

Question 1

What is quantitative inheritance?

Answer 1

Complex disorders & continuous traits, that are influenced by multiple genes and multiple environmental factors

Question 2

What types of gene disorders are deterministic?

Answer 2

Single gene disorders

Question 3

What traits are probabilistic?

Answer 3

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

Continuum of genetic risk -some people will have only a couple of susceptibility alleles that increase risk, others will have all

Question 4

Discuss the liability threshold model

Answer 4

• 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 side of the line represent those with the disorder

Question 5

Discuss the threshed model

Answer 5

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 6

Discuss liability/susceptibility for certain disorders

Answer 6

• 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 7

What is Gaussian distribution?

Answer 7

In probability theory, a normal distribution is a type of continuous probability distribution for a real-valued random variable. The general form of its probability density function is f= 1 σ 2 π e − 1 2 2 The parameter μ is the mean or expectation of the distribution, while the parameter σ is its standard deviation. The variance of the distribution is σ 2. A random variable with a Gaussian distribution is said to be normally distributed, and is called a normal deviate.

Tl;dr: on graph, small to peak back to small

Question 8

Discuss heritability

Answer 8

• Heritability of a trait or disease is the proportion of the total variance that is genetic.
• The overall variance of the phenotype is the sum of the environmental and genetic variance.
• Heritability provides information of the importance of genetic factors in the causation of the disease.

Question 9

Provide some examples of heritability estimates for certain diseases

Answer 9

• Schizophrenia 85
• Asthma 80
• Pyloric stenosis 75
• Ischaemic heart disease 65
• Essential hypertension 60
• Neural tube defect 60

Question 10

What is a mutation in multifactorial disease?

Answer 10

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

Question 11

What are three types of disease causing mutations?

Answer 11

• a. Synonymous polymorphism- changes DNA sequence but not the amino acid or subsequent protein produced
• b. Non-synonymous missense polymorphism- changes DNA sequence and the amino acid and protein produced.
• c Non-synonymous nonsense polymorphism- changes DNA sequence to code a premature stop codon.

Question 12

What is 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

Question 13

What methods have we used to know there is a genetic contribution to disease?

Answer 13

1. Family studies

2. Twin studies

Question 14

What is a flaw of family studies?

Answer 14

This method does not take into account a risk caused by a shared environment such as a familial predilection for hamburgers in siblings

Question 15

Discuss liability curves of affected individuals and their relatives

Answer 15

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

Question 16

Discuss liability of groups with different disease incidence

Answer 16

Males are more prone to her that condition (have a lower liability threshold

Therefore, for a female to be affected, she must be at the high end of the curve (has more contributing genes)

therefore, the children, or siblings, of an affected female are more at risk of having the condition than if she was a he

Question 17

Discuss characteristics of multifactorial inheritance

Answer 17

• 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 18

What are the benefits and flaws of 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

What are the risks of schizophrenia for different twins when related to subject case?

Answer 19

Monozygotic twin - 50%

Dizygotic twin - 15%

Question 20

How do we know whether a polymorphism contributes to a disease?

Answer 20

Association study method

- If there are significantly greater rates disease in those with polymorphism etc

Question 21

Provide an example of the association study method

Answer 21

5A/6A promotor polymorphism in MMP3 (Matrix metalloproteinase 3)

Having a 5A makes you more prone to aortic aneurysm
But
Having a 5A allele only gives you a small increased risk There are other genes involved

Question 22

What are potential problems with association studies?

Answer 22

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
Significant association may be false and due to chance
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 23

How can you analyse as many polymorphisms as you can across the genome in a disease population and a control group and work out which ones are significant?

Answer 23

Test the whole genome

Question 24

What has to be done in association studies after identifying an association?

Answer 24

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

Question 25

CASE STUDY
• John Green comes to see you in the genetic clinic
• He is 24 and worried about his family history of heart disease
What should you consider when dealing with a family history of common disease?

Answer 25

Family history may suggest an inherited predisposition
More affected members
People affected at a younger age
Family history may be caused by a single mutation inherited in a mendelian fashion, but this is rare. If so , gene testing may help
Family history more likely to be caused by a mixture of genetic and environmental factors (multifactorial). Gene testing rarely helps.
Clinical management is usually conventional, targeted at treatable factors

Question 26

CASE STUDY
• John Green comes to see you in the genetic clinic
• He is 24 and worried about his family history of heart disease
How should one deal with this clinically (Ischaemic heart disease)

Answer 26

1. In a very small number of cases there is a single gene disorder causing hypercholesterolaemia. Look for many people affected with very young age of onset of disease
2. More likely to be IHD risk polymorphisms interacting with environmental risk factors.

Question 27

CASE STUDY
• John Green comes to see you in the genetic clinic
• He is 24 and worried about his family history of heart disease
What physiological/genetic considerations are relevant to this case?

Answer 27

1. LDL receptor mutation ?
   • Lipoprotein receptor mutations cause hypercholesterolaemia - ~1000 mutations known
   • Inherited as an autosomal dominant condition
2. Apo E Risk polymorphism ?
   Apolipoprotein E polymorphisms are associated with hypercholesterolaemia
   • polymorphic apolipoprotein • 3 alleles

Question 28

CASE STUDY
• John Green comes to see you in the genetic clinic
• He is 24 and worried about his family history of heart disease
What considerations should you have when predicting heart disease?

Answer 28

• Complex interaction: many environment and genetic factors
• Empirical risk estimates based on:
– Cholesterol
– Blood pressure – Diabetes
– Smoking
– Genetic tests have limited role (LDL receptor mutations)
• Treatment is based on clinical parameters

Question 29

What considerations should you have when considering recurrence rates for multifactorial conditions?

Answer 29

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