Genetics of Common Disease

Question 1

What is mutated in cystic fibrosis?

Answer 1

→ F delta 508
→ Phenylalanine codon is removed

Question 2

What is the inheritance pattern like in Mendelian diseases?

Answer 2

→ Recessive loss of function
→ Autosomal dominant
→ X linked

Question 3

How can you measure intermediate phenotype?

Answer 3

Electrocardiogram

Question 4

What is the intermediate phenotype in people with sudden cardiac death?

Answer 4

→ Heart rate might be slower than it is supposed to be
→ Heart is larger than usual - cardiomyopathy

Question 5

What is the relationship between conduction and heart size?

Answer 5

The larger the heart muscle the longer it takes for conduction because the surface area is larger

Question 6

What does a quivering signal on an ECG look like and why?

Answer 6

→ Ventricular fibrillation
→ Heart muscle gets tired and there is no electrical output

Question 7

What do the P wave and QRS wave mean?

Answer 7

→ P wave - going across the atria
→ QRS - going across the ventricle

Question 8

What is the QT interval associated with?

Answer 8

Highly associated with risk of sudden cardiac arrest

Question 9

What does it mean if the QT interval is longer?

Answer 9

Increased susceptibility of a heart attack

Question 10

Why are twin studies used?

Answer 10

→ 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

Question 11

What percentage is the variation in heart rate due to genetics?

Answer 11

58%

Question 12

What percentage is the variation in QRS down to genetics?

Answer 12

54%

Question 13

What does high heritability imply?

Answer 13

Strong resemblance

Question 14

What is concordance?

Answer 14

How similar a phenotype is

Question 15

What does it mean if there are big differences between MZ twins and DZ twins?

Answer 15

Trait is more genetic than environmental

Question 16

What are SNPs?

Answer 16

→ Variations in a single nucleotide
→ DNA sequence variations that occur when a single nucleotide is altered

Question 17

What is the most common form of variation in the genome?

Answer 17

SNPs

Question 18

What is a genotype?

Answer 18

A pair of alleles at a locus

Question 19

What is a haplotype?

Answer 19

Sequence of alleles along a single chromosome

Question 20

What is a qualitative measure example?

Answer 20

→ Disease status
→ Presence or absence of congenital defect

Question 21

What is a quantitative measure example?

Answer 21

→ Blood glucose levels
→ % body fat
→ Heart rate

Question 22

What is the short term goal of genetic association studies?

Answer 22

Identifying genetic variants that explain differences in phenotype among individuals

Question 23

What is the long term goal of genetic association?

Answer 23

Inform the process of identifying and delivering better prevention and treatment strategies

Question 24

Why can the SNPs for cardiovascular disease not be in essential parts of the genome?

Answer 24

They do not manifest from birth

Question 25

What is the relationship between linkage disequilibrium and SNP distance?

Answer 25

Linkage disequilibrium between two SNPs decreases with physical distance

Question 26

When do you need fewer SNPs to capture variation?

Answer 26

When LD is strong

Question 27

Why are some variants not recombined?

Answer 27

The regions are physically together

Question 28

How many SNPs does an SNP chip have?

Answer 28

317,000 SNPs

Question 29

Describe how an SNP microarray works

Answer 29

→ 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

Question 30

What are the axes of the graph for testing genetic association?

Answer 30

→ X axis is genotype → Y axis is phenotype

Question 31

What do the dots on the manhattan plot represent?

Answer 31

A variant

Question 32

What do the peaks on the manhattan plot show?

Answer 32

Statistical test has a significant effect

Question 33

Why do you need a lot of people in a GWAS study?

Answer 33

If the genes are numerous and small in effect

Question 34

What are the 3 possibilities when finding a SNP associated with a disease?

Answer 34

→ Causal relationship between SNP and disease → Marker is in linkage disequilibrium with a causal locus → False positive

Question 35

How is the P value set?

Answer 35

→ 0.05/n → n is the number of tests

Question 36

What is linkage disequilibrium?

Answer 36

Linkage disequilibrium is the non-random association of alleles at different loci in a given population

Question 37

Define heritability

Answer 37

A measure of how well differences in people's genes account for differences in their traits

Question 38

What does a heritability close to one indicate?

Answer 38

That almost all of the variability in a trait comes from genetic differences, with very little contribution from environmental factors

Question 39

What percentage of shared genetic variation for MZ, DZ, full siblings and half siblings?

Answer 39

MZ= 100 DZ=50 Full siblings= 50 Half siblings= 25

Question 40

Equation for heritability(h2)

Answer 40

h2 = 2 x (MZ correlation – DZ correlation)

Question 41

What does it mean for h2<0.5?

Answer 41

Environmental influences are more important than genetic component

Question 42

What does h2>0.8 suggest?

Answer 42

A trait highly influenced by genes

Question 43

On genetic susceptibility graph, what does the right side suggest?

Answer 43

→ There are more environmental influences involved → GWAS

Question 44

What does the left side suggest on a genetic susceptibility graph?

Answer 44

Linkage

Question 45

How else can you define linkage disequilibrium?

Answer 45

The difference between the observed frequency of a particular combination of alleles at two loci and the frequency expected for random association

Question 46

What happens to linkage disequilibrium between two SNP as physical distance increases?

Answer 46

Decreases with physical distance as more likely to have a recombination event between them

Question 47

What other factor affects LD?

Answer 47

Region of genome i.e. recombination hot spots

Question 48

What are the advantages of strong LD?

Answer 48

→ Need fewer SNPs to capture variation in a region → Cheaper and easier/quicker to analyse

Question 49

What is Bonferroni correction?

Answer 49

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

Question 50

What are the three possibilities if a SNP is identified as significantly associated with disease?

Answer 50

→ A causal relationship between SNP and disease → Marker is in linkage disequilibrium with a causal locus → False positive

Question 51

What is the standard p-value for GWAS?

Answer 51

5 × 10−8

Question 52

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?

Answer 52

They also have the same shared in utero environment

Question 53

How do you measure genetic susceptibility?

Answer 53

Measure heritability

Question 54

What are the goals of GWAS?

Answer 54

→ 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