Genome wide association studies

Question 1

What types of diseases do rare but high impact alleles cause?

Answer 1

Mendelian disorders

Question 2

What types of diseases do common but low impact alleles cause?

Answer 2

Multifactorial disorders

Question 3

What types of diseases do common but high impact alleles cause?

Answer 3

Mendelian disorders with a heterozygote advantage. Favourable for heterozygotes but cause disease in homozygotes

Question 4

What is linkage disequilibrium?

Answer 4

Non-random association of alleles at two or more loci. A particular grouping of alleles at linked loci occurs more often than by chance

Question 5

How do we determine the max number of haplotypes for a set of loci?

Answer 5

2^x, where x = number of loci being examined

Question 6

How do we determine if loci are showing linkage disequilibrium?

Answer 6

Determine the frequencies of alleles in the population, then use that to calculate the expected frequencies. Then do a Chi square test to determine if the observed frequencies differ significantly from the expected frequencies

Question 7

If the Chi square test was significant, would there be evidence of linkage disequilibrium between the loci?

Answer 7

Yes, if the expected frequencies differ from the observed frequencies, there is a set of alleles inherited together more than what is expected by chance

Question 8

What does D mean in linkage disequilibrium?

Answer 8

The deviation, the magnitude of the disequilibrium

Question 9

What do we usually use as a measurement of linkage disequilibrium?

Answer 9

r^2

Question 10

What does an r^2 of 0 mean for linkage disequilibrium?

Answer 10

Complete equilibrium and random association of alleles at the loci

Question 11

What does an r^2 of 1 mean for linkage disequilibrium?

Answer 11

Complete disequilibrium

Question 12

What are the two factors that will affect how long a region stays in linkage disequilibrium?

Answer 12

Time and distance. Will break down in alleles further apart over time

Question 13

What are two international projects that have focused on documenting genomic variation in different populations?

Answer 13

International HapMap project and the 1000 genomes project. Have identified and mapped millions of SNPs

Question 14

What are haplotype blocks?

Answer 14

Regions in a chromosome with high degree of linkage disequilibrium and little diversity in which alleles are present

Question 15

What defines a haplotype block?

Answer 15

Fewer haplotypes in the population are present than what would be expected by 2^x

Question 16

Why are haplotype blocks useful for studying the association between a SNP and a disease locus?

Answer 16

Since they’re always inherited together and we can use one allele in there to predict the others, we can look at a representative SNP for that block and it cuts down our work

Question 17

Are allele frequencies static across populations?

Answer 17

Not in the slightest. Need to consider the population being studied

Question 18

What does LD LINK do?

Answer 18

Lets us select SNPs in a population and generates a heat map while also calculating r^2 and D. Cooler colours indicate lower r^2 and warmer colours indicate high r^2 and high LD

Question 19

Will the same alleles be in linkage disequilibrium between populations?

Answer 19

Nope. Can be in LD in one population and not the other

Question 20

What are LD maps?

Answer 20

Triangle heat map plots displaying the degree of LD between select SNP loci. Makes haplotype blocks really obvious (strong LD)

Question 21

What would be the ideal end goal of a GWAS study?

Answer 21

Look at every single SNP in the human genome for association with a disease

Question 22

Why don’t we need to look at every single SNP while doing GWAS studies?

Answer 22

Haplotype blocks. Some are in such strong LD that we only need to look for association between 1 or 2 of them from that block to know if there’s association with anything else in that block

Question 23

What are tag/proxy SNPs?

Answer 23

Representative SNPs from a haplotype block

Question 24

What are the two critical advances that have allowed us to do GWAS studies in the first place?

Answer 24

1. Ability to do high throughput SNP genotyping with SNP arrays
2. Knowledge that the genome is comprised of haplotype blocks with strong LD

Question 25

How is genotyping done in GWAS studies?

Answer 25

SNP chip arrays. One for each person and includes >500 000 SNPs on it

Question 26

How is a GWAS study set up?

Answer 26

1. Get a big group of people with the disease, and another big group of people without it
2. Genotype every single individual with SNP arrays
3. Score the allele frequencies in each group

Question 27

How do we determine if a SNP allele and a disease state are associated?

Answer 27

Do a Chi square test to see if the SNP allele and the disease state are independent

Question 28

How do we tell if a SNP and disease state are associated with a Chi square test?

Answer 28

If the test stat > crit value, reject the null and they are associated

Question 29

Why isn’t it always feasible to have the same sample size for both the control and affected groups in a GWAS study?

Answer 29

1. Some people might die before the study is complete
2. Some people could revoke their consent
3. Sometimes can’t recruit enough people for both groups (like if the disease is rare)

Question 30

What is the odds ratio?

Answer 30

Compares the risk of a complex disease in two groups with different genotypes

Question 31

What is the typical odds ratio we see for complex diseases? Why?

Answer 31

1.1 to 1.2, very small increases in risk. Because these alleles alone don’t do much, but they interact with other alleles and the environment

Question 32

How do you select individuals for your case group?

Answer 32

Select those that will best be able to find the associations, like the most severely affected, familial history, early age of onset

Question 33

How do you select individuals for your control group?

Answer 33

Select those with similar sex, age, and demographics to the case group, but are at the lowest risk of developing the disease

Question 34

What’s the most common way to display the results of a GWAS study?

Answer 34

Manhattan plot

Question 35

How do we interpret a Manhattan plot?

Answer 35

All the SNPs on the array are arranged by chromosome on the x-axis. The y-axis is the negative log of the p-value for every Chi square test. Threshold for significance is defined. Look for any SNPs above that threshold