Association studies

Question 1

What is lod score?

Answer 1

The strength of evidence for linkage.

Z > 3 (linkage)
Z < -2 (no linkage)

Question 2

What is a genome scan?

Answer 2

Testing markers evenly spaced across the entire genome (every 10cM, ~400 markers)

Question 3

What is the parametric method of linkage mapping?

Answer 3

Estimates the RF between a marker locus and an unobserved trait locus.

Question 4

What is the non-parametric method of linkage mapping?

Answer 4

Counts the number of alleles 2 affected siblings share identical by descent (IBD) - if marker linked to disease locus, the affected sibs more likely to share the disease allele

Question 5

What is multipoint linkage mapping?

Answer 5

Uses several markers at once to localise a disease gene relative to the other markers in the map (more efficient)

Question 6

What are association studies?

Answer 6

Detect the association between genetic variants and disease across families (using LD). More appropriate for complex disease

Question 7

What is a population based association study?

Answer 7

Compare frequency of genetic components of affected subjects (cases) with unaffected subjects (controls)

Question 8

What is a family based association study?

Answer 8

Uses a transmission disequilibrium test (TDT) to compare the distribution of the transmitted allele to the distribution of the non-transmitted allele from parents

Question 9

What is TDT?

Answer 9

• Transmission disequilibrium test
• studies the transmission of alleles from Het parents to affected children
• Tests if there is deviation from Mendelian - if distortion suggests an etiologic association between the allele and the disease

Question 10

What are the advantages and disadvantages of population based association studies?

Answer 10

Advantage:

• powerful to detect relatively small genotypic effects, even in small samples of cases and controls
• easy to collect

Disadvantage:
- population stratification: if there are underlying differences in the cases and controls that are unrelated to disease risk, false positive results are more likely

Question 11

What are the advantages and disadvantages of family based association studies?

Answer 11

Advantage: resistant to potential bias from population stratification

Disadvantage: requires at least one parent being het at the marker being tested

Question 12

What are the differences between linkage and association studies?

Answer 12

• Linkage employs family data and population employs population or family data
• Linkage studies the distance between a marker and a disease locus, whereas Association studies the direct correlation between a certain allele and phenotype

Question 13

What is allelic association?

Answer 13

Where the trait correlates with marker alleles in population. Markers remain in LD with the ‘founder’ mutation over many generations. Association = same ancestral origin

Question 14

What are the 3 forms of allelic association?

Answer 14

1. Direct association: mutant or ‘susceptible’ polymorphism; allele of interest is itself involved in phenotype
2. Indirect association: allele itself is not involved, but nearby correlated gene changes phenotype
3. Spurious association: apparent association not related to genetic aetiology; including population stratification

Question 15

What is the difference between LD and allelic association?

Answer 15

LD is a correlation between (any) markers in a population. Allelic association is correlation between marker allele and trait.

Question 16

What is the most off-cited reason for lack of association replication?

Answer 16

Population stratification

Question 17

What are solutions to population stratification?

Answer 17

1. Family based controls

2. Genetic control: look for evidence of background population substructure and account for it

Question 18

What is LD mapping?

Answer 18

Looking for a variant allele in LD with disease. E.g. If most affected individuals in a population share the same mutant allele, then LD can be used to locate the chromosomal region harbouring the mutant allele

Question 19

What are the 2 important concepts of LD mapping?

Answer 19

1. the marker itself is NOT the reason for the disease, but it’s located nearby the disease susceptibility gene
2. The correlation is based on the founder effect (disease allele has been born a long time ago on a certain ancestral chromosome

Question 20

What are haplotypes?

Answer 20

A combination of specific SNPs (alleles) on a chromosome. Within the same haplotype, all genetic markers are inherited together (if one of them is in LD, all of them are)

Question 21

What are the differences in localization of linkage and association analysis?

Answer 21

Linkage yields broad chromosome regions harbouring many genes; resolution comes from recombination events in families; good in terms of needing few markers; poor in terms of finding specific variants

Association yields fine-scale resolution of genetic variants; resolution comes from ancestral recombination events; good in terms of finding specific variants; poor in terms of needing markers

Question 22

What is the difference between linkage mapping and LD mapping?

Answer 22

1. Linkage resulted from recombination events in last 2-3 generations; LD from ancestral recombination
2. Linkage measures co-segregation in pedigree; LD measures co-segregation in a population
3. Linkage detected for markers close to disease; LD detected for markers even closer