Complex Traits Flashcards
What are complex traits?
Coupling genetic factors along with environmental influences
What do association studies include?
transmission disequilibrium testing
case-control association studies
Characteristics of complex diseases
incomplete penetrance
phenocopies
high frequency of disease-causing allele
Relative risk calculation
λ= frequency in relative of affected person/ population frequency
What does a higher λ mean?
The higher the contribution of the genetic component in determining the disease risk
What does an λ of 15 mean?
If you have a sibling that is affected, your risk of being affected is 15x higher
What happens when there is a genetic component involved in disease manifestation?
The liability distribution among siblings of affected individuals shift to the right, signifying an elevated risk for them to develop the disease
Affected sib-pairs method
If the marker locus is linked to trait locus, an excess of shared alleles among affected sib-pairs will be expected
State what affected sib-pair might share and the probabilities
may share 0,1,2 alleles identical by descent with probabilities 0.25, 0.5, 0.25 respectively
What happens if we perform this test for many markers in the genome?
We can identify those that present a distortion in the expected ratio. If the distortion favours the 1 and 2 shared alleles while lowering the % of 0 shared alleles then there might be a linkage between the marker and risk factor
Advantages of affected sib-pairs method
- non parametric analysis eliminates the need for specifying allele frequencies or inheritance patterns
- provides a precise location of the disease gene
- initial insight into the localisation of risk factors on the chromosome
Disadvantages of affected sib-pairs method
- limited power compared to parametric methods
Linkage disequilibrium
The non-random association in a population of alleles at closely linked loci: tendency of alleles that are close on the same chromosome to be co-inherited throughout generations
Why do markers near a risk factor tend to be inherited together?
Because the same chromosome block is maintained across generations due to limited recombination in chromosomal regions
Where does recombination frequency take place?
At specific positions
How is the genome organised?
In specific haplotype blocks conserved throughout generations
What do the red squares show in a linkage disequilibrium map of a chromosome?
1:1 relationship in terms of linkage disequilibrium
The redder the squares the higher the LOD score
What does maximum linkage disequilibrium mean?
2 loci are always segregating
What does it mean when we see a triangle in a linkage disequilibrium map of a chromosome?
All the loci that are underneath are in linkage disequilibrium
What does the transition from one triangle to the next in a linkage disequilibrium map of a chromosome mean?
A hotspot for crossing over event
How many SNPs are required for genome wide association studies?
500,000 non-African SNPs
1,000,000 African SNPs
Why are more African SNPs required?
The African genome is heterogenous: it is more ancient and therefore there was more time to create new recombinations and new haplotype blocks
What is the difference between linkage and association?
Association is a relation between alleles while linkage is a relation between loci.
What is case-control study?
2 populations: one is the case, individuals affected by a specific disease and the other one is control, healthy individuals
Odds ration
ad/bc= OR
What are the best samples for linkage disequilibrium mapping?
Genetically isolated populations
younger populations
What does a positive associate imply?
A direct causal effect
Linkage disequilibrium
Population stratifaction
Describe the importance of the ApoL1 gene
Mutations in this gene causes African Americans to be more susceptible to kidney disease [characterised by the presence of G1 and G2 haplotypes]. However, ApoL1 has been positively selected as it gives resistance to a trypanosoma infection.
Furosemide
A sodium transport blocker to reduce the transport of sodium due to uromodulin mutation
Why did Homo sapiens have a selection of keeping the risk variant of uromodulin?
The pressure that has kept this SNP variant associated with high expression level in nowadays population is selection against UTIs
What is used to calculate the polygenic risk score PRS?
Different genome-wide association studies
What is polygenic risk score?
If we have a number of loci, each of them with a risk allele, they can be combined using genome-wide polygenic risk scores
What happens if the polygenic risk score is clinically relevant?
We have a tool that associates a genetic risk for a specific disease that can be calculated for each individual
Transmission Disequilibrium Test study
to examine the transmission of a particular allele at a locus from heterozygous parents to their affected offspring: depends on alleles being transmitted in trios
What should we see if a marker is not close to a risk factor?
We should see that the transmission to the affected individual should be the same for the alleles of both parents
What is the aim of the Transmission Disequilibrium Test study?
To find the frequency of the transmitted allele relative to the non-transmitted allele
What does it mean if the numbers are comparable to each other in a Transmission Disequilibrium Test study?
It is probably not a risk factor
What does it mean if the numbers are skewing to each other in a Transmission Disequilibrium Test study?
The allele more frequently transmitted is a risk factor
