Genetics of Common Disease Flashcards
What is mutated in cystic fibrosis?
→ F delta 508
→ phenylalanine codon is removed
What is the inheritance pattern like in mendelian disease?
→ Recessive loss of function
→ Autosomal dominant
→ X linked
How can you measure intermediate phenotype?
→ Electrocardiogram
What is the intermediate phenotype in people with sudden cardiac death?
→ Heart rate might be slower than it is supposed to be
→ heart is larger than usual - cardiomyopathy
What is the relationship between conduction and heart size?
→ The larger the heart muscle the longer it takes for conduction because the surface area is larger
What does a quivering signal on an ECG look like and why?
→ Ventricular fibrillation
→ Heart muscle gets tired and there is no electrical output
What do the P wave and QRS wave mean?
→ P wave - going across the atria
→ QRS - going across the ventricle
What is the QT interval associated with?
→ Highly associated with risk of sudden cardiac arrest
What does it mean if the QT interval is longer?
→ Increased susceptibility of a heart attack
Why are twin studies used?
→ twins are genetically identical
→ non identical twins are not genetically identical but the environment is the same
→ this enables you to eliminate the environment as a confounding factor
What percentage is the variation in heart rate due to genetics?
→ 58%
What percentage is the variation in QRS down to genetics?
→ 54%
What does high heritability imply?
→ Strong resemblance
What is concordance?
→ How similar a phenotype is
What does it mean if there are big differences between MZ twins and DZ twins?
→ Trait is more genetic than environmental
What are SNPs?
→ Variations in a single nucleotide
→ DNA sequence variations that occur when a single nucleotide is altered
What is the most common form of variation in the genome?
→ SNPs
What is a genotype?
→ A pair of alleles at a locus
What is a haplotype?
→ Sequence of alleles along a single chromosome
What is a qualitative measure example?
→ Disease status
→ Presence or absence of congenital defect
What is a quantitative measure example?
→ Blood glucose levels
→ % body fat
→ heart rate
What is the short term goal of genetic association studies?
→ Identifying genetic variants that explain differences in phenotype among individuals
What is the long term goal of genetic association?
→ Inform the process of identifying and delivering better prevention and treatment strategies
Why can the SNPs for cardiovascular disease not be in essential parts of the genome?
→ They do not manifest from birth
What is the relationship between linkage disequilibrium and SNP distance?
→ Linkage disequilibrium between two SNPs decreases with physical distance
When do you need fewer SNPs to capture variation?
→ When LD is strong
Why are some variants not recombined?
→ The regions are physically together
How many SNPs does an SNP chip have?
→ 317,000 SNPs
Describe how an SNP microarray works
→ Run 12 samples
→ Each of the wells has tags for 300,000 variants
→ they are stuck to the base of the chip
→ DNA is run across the chip
→If the DNA has the variant it binds to it
→ fluorescent dye binds
What are the axes of the graph for testing genetic association?
→ X axis is genotype
→ Y axis is phenotype
What do the dots on the manhattan plot represent?
→ A variant
What do the peaks on the manhattan plot show?
→ statistical test has a significant effect
Why do you need a lot of people in a GWAS study?
→ If the genes are numerous and small in effect
What are the 3 possibilities when finding a SNP associated with a disease?
→ Causal relationship between SNP and disease
→ Marker is in linkage disequilibrium with a causal locus
→ false positive
How is the P value set?
→ 0.05/n
→ n is the number of tests
What is linkage disequilibrium?
→linkage disequilibrium is the non-random association of alleles at different loci in a given population.
Define heritability
→a measure of how well differences in people’s genes account for differences in their traits.
What does a heritability close to one indicate?
→that almost all of the variability in a trait comes from genetic differences, with very little contribution from environmental factors.
What percentage of shared genetic variation for MZ, DZ, full siblings and half siblings?
MZ= 100
DZ=50
Full siblings= 50
Half siblings= 25
Equation for heritability(h2)
h2 = 2 x (MZ correlation – DZ correlation)
What does it mean for h2<0.5?
Environmental influences are more important than genetic component
What does h2>0.8 suggest?
→A trait highly influenced by genes
On genetic susceptibility graph, what does the right side suggest?
→there are more environmental influences involved
→GWAS
What does the left side suggest on a genetic susceptibility graph?
Linkage
How else can you define linkage disequilibrium?
→the difference between the observed frequency of a particular combination of alleles at two loci and the frequency expected for random association.
What happens to linkage disequilibrium between two NPS as physical distance increases?
→decreases with physical distance as more likely to have a recombination event between them.
What other factor affects LD?
region of genome i.e. recombination hot spots.
What are the advantages of strong LD?
→need fewer SNPs to capture variation in a region
→cheaper and easier/quicker to analyse.
What is Bonferroni correction?
If the number of tests (SNPs genotyped) is n, we set the threshold to be 0.05/n so that we can avoid including false positives in our findings.
What are the three possibilities if a SNP is identified as significantly associated with disease?
→a causal relationship between SNP and disease
→marker is in linkage disequilibrium with a causal locus
→False positive
What is the standard p-value for GWAS?
5 × 10−8
Dizygotic twins, as with siblings in general, share on average 50% of their genome with each other. However dizygotic twins usually share a little bit more of their genetic variation than other types of siblings – why?
they also have the same shared in utero environment
How do you measure genetic susceptibility?
Measure heritability
What are the goals of GWAS?
→Identify genetic regions that explain differences in phenotype among individuals in a study population
→To identify genetic variants that can be measured to determine whether an individual is at higher risk of disease
→To identify potential drug targets to treat the disease
