Genetics of Complex Diseases- Lecture 47-48

Question 1

The _____ is the extent to which the expression of a common disease is dependent on genetic variation, which can be estimated through ____.

Answer 1

heritable component

family studies

Question 2

What is the equation for calculating heritability?

Answer 2

h^2 = 2 ( r(mz) - r (dz) )
where r(mz) is the correlation for monoxzygotic twins and r(dz) is the correlation for dizigotic twins

Question 3

What is the range of heritability as per the equation?

Answer 3

0 (no heritable component)

1 (completely heritable with no measurable environmental impact)

Question 4

What study methods are available to identify variants that are associated with increased risk for disease?

Answer 4

case-control association study

GWAS (genome-wide assoication study)

Question 5

Describe the steps of a case-control association study.

Answer 5

1- obtain genotypes at genomic position of interest in a group of individuals with the disease and in a matched cohort of unaffected
2- count alleles in each group to determine differences in frequency of specific allele between the two groups
3- use the odds ratio to calculate the effect size (impact)

Question 6

What is required to perform a case-control association study?

Answer 6

a candidate gene that you believe to be associated with a phenotype

Question 7

How do you calculate the odds ratio (OR)?

Answer 7

= ( Allele1(ds) / Allele2(ds) ) / ( Allele1(c) / Allele2(c) )

Question 8

How do you interpret the odds ratio?

Answer 8

OR < 1 protective mutation
OR = 1 neutral (no relationship)
OR > 1 predisposition mutation

Question 9

Describe the steps of a GWAS.

Answer 9

1- collects allele frequency data from common variants distributed across the entire genome in large cohorts of cases and controls
2- p-values for each variant are plotted as a function of genomic location to generate Manhattan plot
3- look for medications/treatments that could act on the mechanisms associated with the most correlated SNP

Question 10

List some of the limitations of

GWAS.

Answer 10

requires large cohort size
missing heritability
misinterpretation of results

Question 11

What is a haplotype?

Answer 11

a series of alleles along the same segment of a chromosome strand
can be linked (alleles that are closer together tend to co-sergregate and are inherited together) or unlinked (alleles further apart with higher likelihood they will be separated during recombination –> lower likelihood they will be inherited together)

Question 12

What is lineage equilibrium?

Answer 12

haplotype frequencies in a population are different from allele (SNP) frequencies due to the loci that are not linked

Question 13

What is linkage disequilibrium?

Answer 13

haplotype frequencies in a population are same or close to allele (SNP) frequencies due to the loci being linked

Question 14

Describe a LD score.

Answer 14

reflects how linked or not linked the loci are in a haplotype
if score is 0% it is not linked (haplotypes at equilibrium)
if score is at 100% they are linked (haplotype frequencies are at complete disequilibrium)