T2: Multifactorial disorders

Question 1

How can we establish whether a multifactorial disease has a genetic component?

Answer 1

1. Twin studies - Using dizygotic (non-identical) twins and monozygotic (identical) twins who have had a similar environment. Monozygotic twins have a shared genome, dizygotic twins has shared half a genome. If there is an increase in concordance between identical twins over non-identical twins, there is evidence of a genetic component.
2. Family clustering - In order to remove bias we identify every individual case a commission is aware of, regardless of whether they have relatives that have it. Then you would calculate the risk to their siblings and compare this to population risk. In cluster headaches we have done this and have seen it is a Mendelian condition.

Question 2

Using schizophrenia as an example, explain what a multifactorial disease is?

Answer 2

There is an element of both a genetic and environmental cause for the disease. There is a 9 fold risk of developing schizophrenia when your siblings have it. There is 48% concordance with identical twins, compared to 17% with fraternal twins. This shows a very substantial genetic component. However 52% do not, even though they share 100% of their genome, there is a significant environmental component.

Question 3

Using Alzheimer’s disease as an example, explain how an individual can inherit susceptibility?

Answer 3

Alzheimer’s is the most common form of dementia. The symptoms include an inability to cope, loss of memory and brain damage. Neurology shows a shrinkage of the brain and tangles of beta amyloid protein in nerve fibres in the hippocampus.

APOE is thought to be a chaperone protein - it helps fold other proteins. Highly functioning APOE helps neurons to fold the beta amyloid and get rid of it. A high functioning APOE is therefore protective against Alzheimer’s and a low functioning APOE is a risk factor. It exists in 3 forms: E2, E3 and E4.

E4 seems to be less effective. A risk factor of Alzheimer’s. Therefore a halpotype of E4 increases susceptivity.

Question 4

What is a Genetic association study?

Answer 4

A genetic association study aims to test whether a given sequence, such as a region of a chromosome, a haplotype, a gene, or an allele, has involvement in controlling the phenotype of a specific trait, metabolic pathway, or disease.

We do this by using a control and patients - they must be a like in everyway except the disease. You then look for differences. You could look for the allele. Association method provides greater power to detect common genetic variants conferring susceptibility to complex phenotypes.

We can look at SNPs and look for differences between cases and control. It will detect if one of the SNP is linked to something causing the disease. We can genotype lots of SNPs at once.

Question 5

What is linkage disequilibrium?

Answer 5

Linkage disequilibrium (LD) is the correlation between nearby variants such that the alleles at neighboring polymorphisms (observed on the same chromosome) are associated within a population more often than if they were unlinked. Therefore a SNP a hundred kilobases away from the gene causes the disease linked to it due to linkage disequilibrium.

Question 6

What is concordance?

Answer 6

Concordance, as used ingenetics, usually means the presence of the same trait in both members of a pair of twins. However, the strict definition is the probability that a pair of individuals will both have a certain characteristic, given that one of the pair has the characteristic.