Genetic Basis of Multifactorial Disease Flashcards
What factors are involved in determining risk of disease ?
A combination of:
- Genetic factors
- Environmental factors
Cystic Fibrosis
Combination of:
- Mainly genetic factors (known mutations in the CF gene)
- Environmental (treatment)
Heart Disease
Combination of:
- Genetic factor (cholesterol handling, blood pressure etc.)
- Environmental component (Diet, Smoking, Exercise)
Fractured neck of femur
Combination of:
- Genetic factor (bone density, balance, weight)
- Mainly environmental (diet, ice on path, age)
Quantitative Inheritance
Complex disorders & continuous traits, are influenced by multiple genes and multiple environmental factors.
Single gene disorders
Deterministic
Incredibly rare
Complex Traits
Probabilistic
Even if have all susceptibility alleles, disease still depends on whether encounter certain environmental hazards.
Continuum of genetic risk
Some people will have only a couple of susceptibility alleles that increase risk, others will have all.
Liability Threshold Model
Liabilities of all individuals in a population form a continuous variable.
Individuals on the RHS of the threshold represent those with the disorder.
Liability
All the factors that influence the development of a multifactorial trait/disorder can be considered as a single entity.
Threshold Model
For a discontinuous phenotype (affected V unaffected) with an underlying continuous distribution, a threshold exists above which abnormal phenotype of expressed.
Susceptibility
Outcome of interaction of many genetic and environmental risk variants.
Population incidence
Proportion beyond the threshold in the general population.
Amongst relatives, the proportion beyond the threshold is the familial incidence.
Heritability
The heritability of a trait or disease is the proportion of the total variance that is genetic.
What is the overall variance of the phenotype ?
The sum of environmental and genetic variance.
Function of heritability
Heritability provides information of the importance of genetic factors in the causation of the disease.
Schizophrenia - genetic component %
85%
Asthma - genetic component %
80%
Pyloric stentosis - genetic component %
75%
Ischaemic Heart Disease - genetic component %
65%
Essential hypertension - genetic component %
60%
Neural tube defect - genetic component %
60%
Mutation
A gene change that causes a genetic disorder (a disease-causing mutation)
Synonymous polymorphism
Changes DNA sequence but not the amino acid OR subsequent protein produced.
Non-synonymous missense polymorphism
Changes DNA sequence, amino acid and protein produced
Non-synonymous nonsense polymorphism
Changes DNA sequence to code a premature stop codon.
Polymorphism facts
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)
How do we know there is a genetic contribution to a disease ?
- Family studies
- Twin studies
Family Studies
Is it more common in relatives of those who are affected ?
Downfall of family studies
This method does not take into account a risk caused by a shared environment.
e.g. family linking for hamburgers
Difference between liability curves for males and females
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.
Describe the liability curve for relatives of the affected
Shifted to the RHS
So, familial incidence is higher than the general population incidence
Characteristic of multifactorial disease
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.
Why do polygenic threshold characters tend to run in families ?
As affected individuals have relatives that share their genes with them.
Feature of twin studies
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.
Monozygotic twins
Share all of their genes
Dizygotic twins
Share on average 50% of their genes
Twin studies in schizophrenia
Monozygotic twins - 50%
Dizygotic twins - 15%
Polymorphism definition
Variations across the genome
Polymorphisms may be neutral or affect gene function.
How to work out if a disease phenotype has a genetic contribution to its causation ?
Recurrence risk in siblings
Twin studies
Association study method
Probability
Finding particular polymorphisms in particular genes, looking across the genome.
Are there more in affected vs non-affected.
Potential problems with association studies
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
When might significant associations be false ?
Due to chance
Due to the population stratification (control group not matched to affected group)
Function of testing the whole genome
Analyse as many polymorphisms as you can across the genome in a disease population and a control group.
Work out which ones are significant.
What can cause family history ?
Likely to be caused by a mixture of genetic and environmental factors.
Gene testing rarely helps.
What might family history suggest ?
An inherited predisposition
Ischaemic Heart Disease - causes
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.
LDL receptor mutation
Lipoprotein receptor mutations cause hypercholesterolaemia
Inherited as an autosomal dominant condition.
Apo E risk polymorphism
Associated with hypercholesterolaemia
What are empirical risk estimates based on ?
- Cholesterol
- Blood Pressure
- Diabetes
- Smoking
Predicting risk of heart disease
- Complex interaction (genetic/environmental factors)
- Empirical risk estimates
- Genetic tests (limited role)
Treatment is based on clinical parameters.
More affected relatives result
Higher recurrence risk
For multifactorial conditions what causes a higher recurrence risk ?
More affected family members
More severely affected family members
How is the risk of recurrence calculated ?
Empirically
Gene tests rarely help unless there is a monogenic form of disease.
