genetic basis of multifactorial disease

Question 1

what two factors contribute to the presentation of a phenotype

explain the example of cystic fibrosis

explain the example of heart disease

Answer 1

the contribution between gentic factors and environmental factors which leads to a particular presentation of a phenotype

cystic fibrosis:
- there is a known mutation in the cystic fibrosis transmembrane regulator gene
- however there is also an impact on the type of treatment

heart disease:
- genetic component and underlying risk factors such as high cholesterol, high blood pressure etc. which cause angina or myocardial infarction
- environmental component is diet, smoking, exercise

Question 2

how are single gene disorders defined?

Answer 2

Single gene disorders = deterministic

Question 3

how are complex traits defined?

Answer 3

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

Question 4

what is the continuum of genetic risk?

Answer 4

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

Question 5

what is liability?

Answer 5

liability: all the factors which influence the development of a multifactorial trait/disorder can be considered as a single entity

Question 6

describe the liability threshold model

what is the population incidence?

Answer 6

• liabilities of all individuals in a population form a continuous variable
• individuals on the right side of the line represent those with the disorder:
• individuals to the left have a certain risk, but do not present:

population incidence is the proportion beyond the threshold in the general population

Question 7

describe susceptibility with the example of a cleft palate

Answer 7

1. every embryo has a certain susceptibility to cleft palate (failure of correct facial developmental processes)
2. the susceptibility is high or low and follows a Gaussian distribution in the general population^
3. if the susceptibility exceeds a critical threshold, the embryo will develop cleft palate
4. susceptibility is the outcome of interaction of many genetic and environmental risk variants in utero

Question 8

what is heritability of a trait/disease?

what is the overall variance?

what does heritability provide information for?

what do high genetic components mean?

Answer 8

• Heritability of a trait or disease is the proportion of the total variance that is genetic (genetic vs environmental components)
• 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.
• high genetic components meaning the next generation is likely to inherit

Question 9

define mutation

Answer 9

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

Question 10

define synonymous polymorphism

Answer 10

synonymous polymorphism: changes DNA sequence but not the amino acid or subsequent protein produced

Question 11

define non-synonymous missense polymorphism

Answer 11

non-synonymous missense polymorpism: changes DNA sequence and the amino aid and protein produced

Question 12

define non-synonymous nonsense polymorphism

Answer 12

non-synonymous nonsense polymorphism: changes DNA sequence to code a premature stop codon

Question 13

give the 2 definitions of polymorphism

Answer 13

variations across the genome: 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 disease in its own right. it may however, predispose to a common disease ie. it is a risk factor

Question 14

what is used to determine whether there is a genetic contribution to a disease?

Answer 14

family studies and twin studies

if a disease pattern is seen within a family, it is likely there is a higher genetic component

Question 15

what do family studies not take into account?

how do liability curves for relatives differ from normal population liability curves?

Answer 15

however family studies do not take into account risk caused by a shared environment such as a familial preference for hamburgers in siblings

liability curves of affected and their relatives: the curve for relatives of affected will be shifted to the right so the familial incidence is higher than the general population incidence (probabiliy of getting disease is higher in these families which have a shared higher risk)

Question 16

describe the liability curve of those with ischaemic heart disease?

Answer 16

• males are more prone to get the condition (i.e they 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

characteristics of multifactorial inheritance:

why do polygenic threshold characters tend to run in family?

what do parents with severally affected children have more of?

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 percentage of genes do monozygotic twins share?

what percentage of genes do dizygotic twins share?

what do twin studies not take into account?

Answer 18

• monozygotic twins share all their genes, dizygotic twins share an average of 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 2 ways of working out if a disease phenotype has a genetic contribution?

Answer 19

• Recurrence risk in siblings
• Twin studies

Question 20

what is used to find out whether a polymorphism contributes to a disease?

Answer 20

association study method:

• looking at large data sets and trying to pin point if any small DNA changes are the usual single base pair changes in DNA are associated overall together or individually with a certain disease
• affected cases are going to have more of this DNA change in relation to non-affected cases: affected cases will have a higher incidence of these polymorphisms than the non-affected cases

Question 21

what is an example of an individual change in DNA which causes phenotype?

Answer 21

example of an individual change in DNA which causes phenotype:5A/6A promotor polymorphism in MMP3

• Having a 5A (5 allele within MMP3) 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 problem 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 (false negatives)
• 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 (might be true in one population group but not in other cases)