Genetics 9 - Common disorders and multifactorial inheritance & Genetics of Complex
traits
Anil Chopra
1. Explain the concept of genetic susceptibility to common disease.
Monogenic Disease
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One mutated gene (although multiple mutations are possible).
Mutation causes defective protein.
If you have mutation you get disease (depending on whether it is dominant or recessive).
All people with the disease have the mutated gene.
For a complex trait, no single gene can cause the disease, the cause is multifactorial.
This is caused by a number of genes known as disease susceptibility genes.
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Multifactorial – genes plus environment.
No single gene causes disease.
Threshold effect – non-linear relationship between gene number and disease expression.
Low penetrance.
Gene-gene interactions (epistasis).
Genes are not defective – promote susceptibility to disease.
Most common diseases are complex traits eg cancer, heart disease, diabetes.
Complex traits are focussed around a different concept of disease gene – disease
susceptibility loci – polymorphic variants which may function slightly differently.
Multiple genes give potential for continuously variable phenotype.
It is the combination of susceptibility genes (above a threshold number) that gives
predisposition (susceptibility) to disease.
Environment causes disease – you don’t get a disease unless you are genetically
predisposed but you still need an environmental trigger.
Because they are caused by a variety of different genes, it allows for there to be
varying degrees of susceptibility. This usually forms a continuous distribution.
2. Describe the susceptibility/threshold model.
There is also a threshold level above which the disease is caused and reaching it
requires certain genes as well as environmental effects.
 The more susceptibility genes you have, the closer you are to the threshold level.
 There is usually some kind of environmental trigger needed to cause the disease
and depending on the intensity of the trigger, the disease can be more or less
affected e.g. smoking, nuclear reactors. This affects the threshold level above
which the disease.
3. Define how we determine whether a multifactorial disease has a genetic
component?
We can determine whether a multifactorial disease has a genetic component in various
ways:
 Adoption studies: if the adopted children develop the same diseases as their
biological parents, the disease is genetic, whereas if they develop the same
diseases as their adopted parents, then the disease has environmental triggers.
 Immigration studies: if immigrants get new diseases, then those diseases must be
environmental, whereas if they get the same diseases as those in their home
country, then it must be genetic.
 Family studies: using lambda S values. s values for complex traits is low!
s = risk to siblings of patients
population prevalence
 Twin Studies: study the concordance between twins to see if they get the same
diseases.
4. Discuss the concept of candidate genes.
In an association study, in order to find the gene that you think is associated with the
particular disease you need to look at three aspects:
 FUNCTION
(RELEVANCE)
 POSITION
(LINKAGE STUDY)
 EXPRESSION (CORRECT TISSUE)
5. Explain association studies.
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These look at the association of a chosen candidate allele with a disease – compared to
controls.
Whole populations are investigated.
Control group critical and must be carefully selected to control for patient population
age matched
sex matched
ethnicity matched
environment matched
It can then be ensured that difference in allele frequency in patient population is due to
disease.
Generally testing candidates for linkage disequilibrium.
Non-familial (linkage studies focus on concordant inheritance/ family)
Not powerful – depends on functional polymorphisms.
6. Discuss autoimmune disease as an example of complex inheritance
Autoimmune diseases: this is an immune response to a “self-antigen” which does not
resolve due to the continuous presentation of antigen. E.g. Insulin dependent diabetes
mellitus, rheumatoid arthritis, multiple sclerosis, Crohn’s disease and systemic lupus
erythematosus.
- General genes can give susceptibility to autoimmune disease
- There are also specific disease genes.
- Multiple diseases present in families