Multifactorial Inheritance 04.10.22

Question 1

What is multifactorial?

Answer 1

• Diseases that are due to a combination of genetic and environmental factors
• Most common diseases are multifactorial

Question 2

How do we identify that a condition has a genetic component?

Answer 2

By clinical observation:
- Family studies
- Twin studies
- Adoption studies

Question 3

How do we carry out a family study?

Answer 3

• compare the incidence of a disease amongst the relatives of an affected individual with the general population

Question 4

What effects does a MF condition have?

Answer 4

• risk of the condition in relatives of an affected individual is dramatically higher than in the general population
• the risk varies directing with the degree of genetic relationship (e.g high chance with sibling)
• risk varies with the severity of the proband’s illness
• risk varies with the number of relatives affected

Question 5

Example: Risks of Schizophrenia for relatives

Answer 5

Risk is much higher when there is a first-degree relationship compared to second and third
E.g. If your parent has Sc then you have a 5.6% chance of getting it
E.g. If you have a child with Sc then you have a 12.8% chance of getting it

Question 6

What is a twin study using concordance rate?

Answer 6

• Compare genetically identical (Monozygotic) with genetically non-identical (Dizygotic) twins
• Concordance rate is the % of twin pairs studied that both have the condition
• If a condition has a genetic component then you would expect the concordance rate to be higher in MZ than DZ twins.
• concordance rate gives a rough figure for the heritability of a MF disorder
• environmental things will have a low concordance rate between twins e.g. car accident, being shot etc…

Question 7

What are adoption studies?

Answer 7

• adopted children of a parent with a MF condition have a high risk of developing the disease
• an adopted parent and child will have a low risk whereas adopted child and biological child will still have a high risk

Question 8

What is hereditability?

Answer 8

• Proportion of the causes of a condition that can be linked to genetic factors as opposed to environmental factors
• Expressed as a proportion of 1 or as a percentage
• one way to calculate is using the concordance rate in MZ twins.

Question 9

What are the characteristics of Multifactorial Inheritance?

Answer 9

• incidence on the condition is greatest amongst relatives of the most severely affected patients
• risk is greatest for first degree relatives and then decreases rapidly in distant
• if there is more than one affected close relative then the risks for other relatives are increased

Question 10

What happens if a condition is more common in one particular sex?

Answer 10

E.g. Pyloric stenosis.
Males are much more likely to have this disease so if a female has this condition, it probably has something genetic going on.
If a female infant with pyloric stenosis then their brother has a 9.2% chance of having it and sister has 3.8 %.
- If the condition is more common in one particular sex, then relatives of an affected individual of the less frequently affected sex will be at a higher risk than relatives of an affected individual of the more frequently affected sex

Question 11

What is the liability / threshold model?

Answer 11

• Liability: the factors that influence the development of a multifactorial disorder
• The curve for relatives is shifted to the right compared to the general population
• the closer the relationship, the greater the shift to the right
• a threshold exists above which the abnormal phenotype is expressed

Question 12

What is the population and familial incidence?

Answer 12

In the general population, the proportion beyond the threshold is the population incidence and among relatives is the familial incidence

Question 13

What are Genome Wide association studies (GWAS)?

Answer 13

• uses the fact a gene can have several variants (alleles)
• some variants cause disease and are pathogenic some are not
• can sequence an area and try to identify the gene and the particular allele that is associated with the increased likelihood of developing the condition

Question 14

What are polymorphisms?

Answer 14

Genetic variation that still results in a functioning gene e.g. SNP (single nucleotide polymorphisms)

Question 15

Example of GWAS?

Answer 15

Large cohort of prostate cancer patients
- more than 70 common low risk susceptibility loci were identified
- individually each one conferred only a small risk for prostate cancer
- the combined contribution of these common sequence variants explained only about 30% of the heritable risk

Question 16

What is a neural tube defect?

Answer 16

It is a MF condition:
- Defective closing of the developing neural tube during the first month in embryonic life
- Highest in people of celtic origin
- in Ireland 10% cases attributed to mutation in methylenetetrahydrofolate (MTHFR)
- If you have one sibling with a neural tube defect, your risk is increased a lot.

Question 17

If MF disease is due to the interaction of genes with environmental factors, what are the environmental factors?

Answer 17

E.g. environmental agents acting on embryogenesis:
- Drugs and chemicals (thalidomide, alcohol)
- Maternal Infections (rubella, CMV)
- Physical agents (radiation)
- Maternal Illness (diabetes, phenylketonuria)

Question 18

What does the future hold for this?

Answer 18

• Screen our DNA and find out if we are at a higher risk for certain things e.g. diabetes
• Find out of you are a carrier and are at risk of passing it on to children
• Understand your genetic health risks
• Can find out how we may respond to certain medications (chemotherapy)
• VERY controversial as to wether we should be doing this