Genetics of Common Disease Flashcards
Describe some characteristics of Mendelian disease.
- most cases are due to one gene and often the majority are due to one particular mutation (e.g., CysticFΔ508 is a three-base deletion, removing a phenylalanine codon)
- inheritance pattern is clear: recessive loss of function, autosomal dominant, X-linked
- minimal influence from environment
Common diseases are often multi-factorial.
Expand.
Multiple genes may affect the disease. There is also a strong influence of the environment.
Therefore, the effect of every single gene may be negligible.
What is SCD?
SCD stands for sudden cardiac death. This is death from definite or probable cardiac causes within 1 hour of onset of symptoms.
Its incidence from international studies:
- > 50% of all CHD deaths
- up to 20% of all deaths
Describe an ECG.
An ECG can tell us if someone is going to be at an increased risk of cardiac arrest.
Quite a lot of the time, the patient has cardiomyopathy - where the muscle of the heart has grown. Thus, the time for the conduction of the heart will take longer, as there is a bigger surface area.
It’s easy to do an ECG - it’s non-invasive and you can take lots of samples from the general population.
What does SCD ‘look like’ on an ECG?
You can look at the pre-SCD bit of the ECG to see if you can figure out what caused it.
The P wave goes through the atria, and the QRS goes through the ventricles. The QT interval is highly associated with SCD; if there are longer QT intervals, there is an increased susceptibility to SCD.
How would you find out the heritability of ECG indices?
Heritability tells you how much of the variation is down to genetics. The simplest variability test is by looking at twins.
It is estimated by looking at the difference in the correlation of monozygotic (MZ) and dizygotic (DZ) twin pairs. You would give them a score between 0-1.
A high heritability implies a strong resemblance.
How would you interpret twin studies?
Homozygotic twins are usually more similar than the dizygotic twins.
If a trait is more commonly seen in homozygotic twins than dizygotic, this implies that the trait is more likely down to the genetics than the environment.
What are SNPs?
SNPs are DNA sequence variations that occur when a single nucleotide is altered.
SNPs are the most common form of variation in the human genome. They have been catalogued in several databases.
We also know what their frequency might be thanks to the 1000 genome project.
What is a genotype and a haplotype?
Genotype: pair of alleles (one paternal, one maternal) at a locus.
Haplotype: sequence of alleles along a single chromosome.
Describe genetic association studies.
SHORT-TERM GOAL: Identify genetic variants that explain differences in phenotype among individuals in a study population
- Qualitative: disease status, presence/ absence of congenital defect
- Quantitative: blood glucose levels, % body fat, heart rate
If and association is found, then further study can follow to:
- understand mechanism of action and disease etiology in individuals
- characterize relevance and/or impact in more general population
LONG-TERM GOAL: to inform process of identifying and delivering better prevention and treatment strategies
Describe linkage disequilibrium.
In general, linkage disequilibrium between two SNPs decreases with physical distance.
The extent of linkage disequilibrium varies greatly depending on region of genome.
If the linkage disequilibrium is strong, we need fewer SNPs to capture the variation in a region.
Describe SNP chips.
A “typical” SNP chip has at least 317,000 SNPs distributed across the genome. The newest contain ~1 million.
We do not directly measure genotypes at all genetic polymorphisms, but rather rely on association between the polymorphisms we do assay and those which we do not assay.
SNP-SNP association, or linkage disequilibrium, is fundamental to our ability to sample the whole genome with relatively few SNPs.
Describe the technology behind an SNP microarray.
TARGET PREP: you would take you DNA sample, amplify it, and then extract the fragemtn for sequencing
HYBRIDISATION: if the DNA fragment has a variant on the chip, it binds to it in a single-stranded form and they have a fluorescent dye which captures the genotype at that position
LIGATION: the labelled probes are bound to the sample, differentiating between the two alleles
SIGNAL AMPLIFICATION: this is when you stain and image your microarray disc; you make it bright enough and then measure the intensity of the array
What are some characteristics of SNP array results?
- you want a clear colour difference between each genotype
- each of the dots represents a person
- when the colours don’t separate as clearly, you need to perform some statistical tests
How would you test genetic association?
Genetic association in a nutshell is to relate the genotype to the phenotype.
After running and association test for each variation, you’ll get a p-value of how well it fits the data. You then check if a particular variant is associated with people with a faster/slower heart rate (for example).
Then you’d plot it in a Manhattan plot. Each plot represent a variant and an association p-value. The peak shows that a particular variant is really associated with heart rate.
