Genetic Basis of Multifactorial Disease

Question 1

What factors are involved in determining risk of disease ?

Answer 1

A combination of:

• Genetic factors
• Environmental factors

Question 2

Cystic Fibrosis

Answer 2

Combination of:

• Mainly genetic factors (known mutations in the CF gene)
• Environmental (treatment)

Question 3

Heart Disease

Answer 3

Combination of:

• Genetic factor (cholesterol handling, blood pressure etc.)
• Environmental component (Diet, Smoking, Exercise)

Question 4

Fractured neck of femur

Answer 4

Combination of:

• Genetic factor (bone density, balance, weight)
• Mainly environmental (diet, ice on path, age)

Question 5

Quantitative Inheritance

Answer 5

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

Question 6

Single gene disorders

Answer 6

Deterministic
Incredibly rare

Question 7

Complex Traits

Answer 7

Probabilistic

Even if have all susceptibility alleles, disease still depends on whether encounter certain environmental hazards.

Question 8

Continuum of genetic risk

Answer 8

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

Question 9

Liability Threshold Model

Answer 9

Liabilities of all individuals in a population form a continuous variable.

Individuals on the RHS of the threshold represent those with the disorder.

Question 10

Liability

Answer 10

All the factors that influence the development of a multifactorial trait/disorder can be considered as a single entity.

Question 11

Threshold Model

Answer 11

For a discontinuous phenotype (affected V unaffected) with an underlying continuous distribution, a threshold exists above which abnormal phenotype of expressed.

Question 12

Susceptibility

Answer 12

Outcome of interaction of many genetic and environmental risk variants.

Question 13

Population incidence

Answer 13

Proportion beyond the threshold in the general population.

Amongst relatives, the proportion beyond the threshold is the familial incidence.

Question 14

Heritability

Answer 14

The heritability of a trait or disease is the proportion of the total variance that is genetic.

Question 15

What is the overall variance of the phenotype ?

Answer 15

The sum of environmental and genetic variance.

Question 16

Function of heritability

Answer 16

Heritability provides information of the importance of genetic factors in the causation of the disease.

Question 17

Schizophrenia - genetic component %

Answer 17

85%

Question 18

Asthma - genetic component %

Answer 18

80%

Question 19

Pyloric stentosis - genetic component %

Answer 19

75%

Question 20

Ischaemic Heart Disease - genetic component %

Answer 20

65%

Question 20

Essential hypertension - genetic component %

Answer 20

60%

Question 21

Neural tube defect - genetic component %

Answer 21

60%

Question 22

Mutation

Answer 22

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

Question 23

Synonymous polymorphism

Answer 23

Changes DNA sequence but not the amino acid OR subsequent protein produced.

Question 24

Non-synonymous missense polymorphism

Answer 24

Changes DNA sequence, amino acid and protein produced

Question 25

Non-synonymous nonsense polymorphism

Answer 25

Changes DNA sequence to code a premature stop codon.

Question 25

Polymorphism facts

Answer 25

Any variation in the human genome that: - Has a population frequency > 1% - Does not cause disease in its own right - It may however predispose to a common disease (i.e. is a risk factor)

Question 26

How do we know there is a genetic contribution to a disease ?

Answer 26

1. Family studies 2. Twin studies

Question 27

Family Studies

Answer 27

Is it more common in relatives of those who are affected ?

Question 28

Downfall of family studies

Answer 28

This method does not take into account a risk caused by a shared environment. e.g. family linking for hamburgers

Question 29

Difference between liability curves for males and females

Answer 29

Males are more prone to get the condition (have a lower liability threshold) For a female to be affected, she must be at the high end of the curve (has more contributing genes) Children of an affected female are more at risk of having the condition.

Question 30

Describe the liability curve for relatives of the affected

Answer 30

Shifted to the RHS So, familial incidence is higher than the general population incidence

Question 31

Characteristic of multifactorial disease

Answer 31

Polygenic threshold characters tend to run in families. Parents that have several affected children will have more high risk alleles than parents with only 1 affected child. Recurrence risk increases with increasing number of previously affected children.

Question 32

Why do polygenic threshold characters tend to run in families ?

Answer 32

As affected individuals have relatives that share their genes with them.

Question 33

Feature of twin studies

Answer 33

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 34

Monozygotic twins

Answer 34

Share all of their genes

Question 35

Dizygotic twins

Answer 35

Share on average 50% of their genes

Question 36

Twin studies in schizophrenia

Answer 36

Monozygotic twins - 50% Dizygotic twins - 15%

Question 37

Polymorphism definition

Answer 37

Variations across the genome Polymorphisms may be neutral or affect gene function.

Question 38

How to work out if a disease phenotype has a genetic contribution to its causation ?

Answer 38

Recurrence risk in siblings Twin studies

Question 39

Association study method

Answer 39

Probability Finding particular polymorphisms in particular genes, looking across the genome. Are there more in affected vs non-affected.

Question 40

Potential problems with association studies

Answer 40

How do you know what gene to look at ? - need to look at all genes How do you know which polymorphism to look at ? - computer algorithms

Question 41

When might significant associations be false ?

Answer 41

Due to chance Due to the population stratification (control group not matched to affected group)

Question 42

Function of testing the whole genome

Answer 42

Analyse as many polymorphisms as you can across the genome in a disease population and a control group. Work out which ones are significant.

Question 43

What can cause family history ?

Answer 43

Likely to be caused by a mixture of genetic and environmental factors. Gene testing rarely helps.

Question 44

What might family history suggest ?

Answer 44

An inherited predisposition

Question 45

Ischaemic Heart Disease - causes

Answer 45

In a very small number of cases there is a single gene disorder causing hypercholesterolaemia. More likely to be IHD risk polymorphisms interacting with environmental risk factors.

Question 46

LDL receptor mutation

Answer 46

Lipoprotein receptor mutations cause hypercholesterolaemia Inherited as an autosomal dominant condition.

Question 47

Apo E risk polymorphism

Answer 47

Associated with hypercholesterolaemia

Question 48

What are empirical risk estimates based on ?

Answer 48

- Cholesterol - Blood Pressure - Diabetes - Smoking

Question 49

Predicting risk of heart disease

Answer 49

- Complex interaction (genetic/environmental factors) - Empirical risk estimates - Genetic tests (limited role) Treatment is based on clinical parameters.

Question 50

More affected relatives result

Answer 50

Higher recurrence risk

Question 51

For multifactorial conditions what causes a higher recurrence risk ?

Answer 51

More affected family members More severely affected family members

Question 52

How is the risk of recurrence calculated ?

Answer 52

Empirically Gene tests rarely help unless there is a monogenic form of disease.