Multifactorial Inheritance

Question 1

what is multifactorial inheritance?

Answer 1

refers to traits that are caused by a combination of inherited
& environmental factors (not just genetic)
Common Complex Disorders = Multifactorial Disorders

Question 2

what are the effects of DNA variation?

Answer 2

Differences in DNA have varying effects on health.
It depends on where the differences occurs and whether they alter the function of essential genes and /or their controlling elements.

Question 3

what is Mendelian inheritance?

Answer 3

caused by a mutation in one or both copies of a single nuclear gene (monogenic)
It results in classical inheritance patterns:
dominant/recessive
autosomal/X-linked

Question 4

what is non- Mendelian inheritance?

Answer 4

AKA Multifactorial inheritance (common complex conditions) - Inheritance of a condition due to the interaction of variants within your genes (poly genes) with one another (increasing your susceptibility) and the environment.
Maternal inheritance - mitochondrial
Polygenic inheritance

Question 5

how are common complex disorders inherited?

Answer 5

condition due to the interaction of variants within your genes (poly genes) with one another (increasing your susceptibility) and the environment.

You can inherit CCD either via:
- Mendelian inheritance (rare)
- Non-mendelian inheritance (common) (multifactorial inheritance)

Generally, ONE organ system affected

Question 6

how many genes are CCD influenced by?

Answer 6

CCDs are polygenic - they display continuous traits which follow a normal distribution in the population.

Question 7

what are Mendelian conditions?

Answer 7

• Hypercholesterolaemia
• Marfan syndrome
• Cystic fibrosis
• Sickle cell disease
• Duchenne muscular dystrophy

The genetic component becomes clear when looking at pedigree pattern and recurrence risk.

Question 8

what are common conditions due to multifactorial inheritance?

Answer 8

coronary artery disease
diabetes mellitus
Hypertension
Cerebrovascular disease
Schizophrenia
Breast & bowel cancers
Some congenital anomalies

Question 9

why are Mendelian condition said to have a genetic component?

Answer 9

Genetic component is suggested due to clustering of cases in some families but there is no obvious inheritance pattern

Mendelian conditions and common conditions give different observed patterns of recurrence within families.
The effect of environment is more important for common conditions but also important for Mendelian conditions.

Question 10

what are the characteristics of diseases that are more genetic?

Answer 10

rare
high occurrence rate in families
unifactorial (single cause)
genetics simple

Question 11

what are the characteristics of diseases that are more environmental?

Answer 11

common
low recurrence rate
multifactorial
genetics complex

Question 12

how are genetic and environmental influences of a disease worked out?

Answer 12

through observational studies of large groups of people with said disease.
they tell us how variations in a common complex condition can be due to genetic influences or environmental influences.

Question 13

what observational techniques are used to gather evidence on genetic and environmental influences?

Answer 13

familial clustering – working out the relative incidence in the family compared with the incidence within the general population

twin studies – incidence in monozygotic twins compared with dizygotic twins

adoption studies – incidence of disease in monozygotic twins adopted into different families - impact of moving to new environment may alter disease susceptibility

population & migration studies – incidence of disease in a population of a particular ancestry when they move to a new geographical area

Question 14

how would twin studies show whether a trait is genetic or environmental?

Answer 14

example: height and IQ are quite largely but not completely affected by genetic factors.
environmental factors e.g. diet also have an influence.
Determining the incidence of disease in twins helps determine genetic or environmental components within aetiology (causes)
- high concordance in MZ indicates large genetic component
- low concordance in MZ indicates low genetic component, high environmental component

Question 15

what does this suggest about the likelihood of these diseases being due to genetics and environment?

Answer 15

this data suggests that having a family history of CAD will influence the risk of an individual developing it but the biggest risk is related to environmental factors e.g. diets, whether you smoke or exercise etc.

Question 16

what would family studies show about CCD?

Answer 16

probabilities of recurrence of common complex condition are calculated by observing no. of relatives with the same condition in studied families.

Question 17

how do single genes contribute to a continuous character?

Answer 17

here’s how the effect of many different genes controlling the same characteristic add together to control continuous traits:

Question 18

how do genetic and environmental factors combine to produce a liability to multifactorial conditions?

Answer 18

they produce a liability curve that combines both genetic & environmental factors that influence your chance of developing a disease.

Question 19

how does a liability curve work?

Answer 19

Individual start off at a different liability depending on their genetic susceptibility.
E.g. Your genetics place your liability around the middle (average) but the fact that you smoke may push you over the liability threshold and you may develop the multifactorial disorder.
Above a certain threshold liability, a person will develop the multifactorial disorder

Question 20

what is the probability of a relative having the same multifactorial condition as you?

Answer 20

it’s HIGHER because you are more likely to share genes which give you a higher liability for the disease.
But your relative may not get past threshold - depends on the environmental factors.
However again family members are more likely to share the same environment and behaviour e.g. diet.

Question 21

give an example of a CCD and its environmental and genetic factors?

Answer 21

Neural tube defects: Spina Bifida
Environmental factors:
Medication the mother is on can affect pregnancy e.g. medication for epilepsy
Consuming folic acid reduces recurrence risk of neural tube defects.
Genetic factors – obtained via a family tree:
See if other people in the family have spina bifida - possible genetic susceptibility

Question 22

what would a doctor do after information on a CCD is gathered?

Answer 22

Once a doctor has gathered this information, they will give you advice:
manage environmental factors that increase susceptibility of development of disease e.g. change medication
you can’t alter genetic factors

Question 23

how is recurrence risk of multifactorial disorders assessed?

Answer 23

assessed by empirical figures obtained by population studies and not following the pedigree (but you should still take a family history to see if there is anything unusual) e.g. if there are many effected individuals it may not be multifactorial condition but may be due to single gene disorder (rare).

the doctor will then give the patient the empiric risk based on observational studies

Question 24

what is an empiric risk?
how is it used in a clinical setting?

Answer 24

The chance that a disease will occur in a family, based on experience with the diagnosis, past history, and medical records rather than theory (knowledge of the causative mechanism)
E.g. look at a study which records families who have one child with spina bifida to see how many of them have a second child with spina bifida
(Usually around 4% recurrence)
Note this information only applies to studied population. Genetic factors in different populations will be different. So it is important to look at a study that uses the same population the patient resides in.
We then tell the family that if we control environmental risks the chances of another child having spina bifida is 4%

Question 25

when are you more at risk of getting a multifactorial condition?

Answer 25

the further you get away from the individual affected by a multifactorial condition in the family tree the lower the recurrence risk is.
This is because the further away you are the fewer genetic factors you have in common.

Question 26

give a brief summary of the main points for a multifactorial condition?

Answer 26

• Caused by a combination of environmental and genetic factors
• Multiple genes (polygene) with individually small risks are often implicated for genetic predisposition
• Generally, one organ system affected. (in chromosomal conditions multiple organ systems are affected)
• Recurrence risk for multifactorial disorders is assessed by empirical figures obtained by population studies and not following the pedigree (but you should still take a family history to see if there is anything unusual) e.g. if there are many effected individuals it may not be multifactorial condition but may be due to single gene disorder (rare).

Question 27

how are genes for Mendelian disorders identified?

Answer 27

Use the pedigree pattern of multiple families which all have a high prevalence of a condition to work out the mode of inheritance for a disorder.
Then compare common markers in families to try and deduce the specific gene:
Perform linkage studies to see which bits of chromosomes have been inherited by all affected people in the family.
If you have multiple families with same condition you can narrow it down to a specific area of the genome that all affected people have in common to then find the relevant gene.
Can’t do this form common complex disorders.

Question 28

how are genes for CCD identified?

Answer 28

identified through association studies of large families
it relies on the fact that people with the same condition share a particular DNA pattern.

Question 29

how is a genome wide association study used to identify genes in a CCD?

Answer 29

In genome wide association study:
Get thousands of people, split into control group (without condition) and affect group.
Test up to 500,000 SNP in each person by microarray analysis
Compare SNP patterns (e.g. frequency of certain SNP) first between members of the same group to create an average then compare the two groups (see below)
Look for SNPs more/less common in the affected group than control group - SNP may be the factor that influences susceptibility to a disease
However the increased/decreased risks of getting a condition due to a single SNP on single gene are usually low (x1.1 – 1.5 chance of getting a disease).

Question 30

what would the presence of variable effects change in the association study?

Answer 30

They may also have variable effects in individuals due to combinations with other DNA present or absent in other people’s genome.
Therefore other genes and environmental factors are involved.
In future clinical practice SNPS associated with several genes maybe used together to give estimate of susceptibility - but this is very complex
Changes picked up using SNP library
May directly influence a condition
May be indirect association - it is a marker for nearby genetic influences which affect the condition

Question 31

what is the 100,000 genome project?

Answer 31

Government has announced plans to sequence the full genomes of up to 100,000 NHS patients with cancer, rare inherited disease or infectious diseases.
This is to see if we can use this information to influence the management of these conditions.

Question 32

how would the 100,000 genome project help during clinical practice?

Answer 32

Genetic variants can alter drug response - how well people respond to a drug can be dependent on their genetic background e.g. availability of an enzyme.

New therapies are being developed based on genomic information of individual or the disease itself e.g. cancer to see what treatments are more likely to be effective against it.

genomic info used to tell people the risk of developing a disease. E.g. sequence the genome of an individual to see if they are genetically predisposed to any conditions to see they can alter lifestyle factors to prevent or better manage diseases. (may help motivate people if they know they are at risk of a disease to change lifestyle factor. However, in practice this was not seen to change people behaviour e.g. stop them smoking)