Association studies Flashcards
What is lod score?
The strength of evidence for linkage.
Z > 3 (linkage)
Z < -2 (no linkage)
What is a genome scan?
Testing markers evenly spaced across the entire genome (every 10cM, ~400 markers)
What is the parametric method of linkage mapping?
Estimates the RF between a marker locus and an unobserved trait locus.
What is the non-parametric method of linkage mapping?
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
What is multipoint linkage mapping?
Uses several markers at once to localise a disease gene relative to the other markers in the map (more efficient)
What are association studies?
Detect the association between genetic variants and disease across families (using LD). More appropriate for complex disease
What is a population based association study?
Compare frequency of genetic components of affected subjects (cases) with unaffected subjects (controls)
What is a family based association study?
Uses a transmission disequilibrium test (TDT) to compare the distribution of the transmitted allele to the distribution of the non-transmitted allele from parents
What is TDT?
- 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
What are the advantages and disadvantages of population based association studies?
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
What are the advantages and disadvantages of family based association studies?
Advantage: resistant to potential bias from population stratification
Disadvantage: requires at least one parent being het at the marker being tested
What are the differences between linkage and association studies?
- 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
What is allelic association?
Where the trait correlates with marker alleles in population. Markers remain in LD with the ‘founder’ mutation over many generations. Association = same ancestral origin
What are the 3 forms of allelic association?
- Direct association: mutant or ‘susceptible’ polymorphism; allele of interest is itself involved in phenotype
- Indirect association: allele itself is not involved, but nearby correlated gene changes phenotype
- Spurious association: apparent association not related to genetic aetiology; including population stratification
What is the difference between LD and allelic association?
LD is a correlation between (any) markers in a population. Allelic association is correlation between marker allele and trait.
What is the most off-cited reason for lack of association replication?
Population stratification
What are solutions to population stratification?
- Family based controls
2. Genetic control: look for evidence of background population substructure and account for it
What is LD mapping?
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
What are the 2 important concepts of LD mapping?
- the marker itself is NOT the reason for the disease, but it’s located nearby the disease susceptibility gene
- The correlation is based on the founder effect (disease allele has been born a long time ago on a certain ancestral chromosome
What are haplotypes?
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)
What are the differences in localization of linkage and association analysis?
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
What is the difference between linkage mapping and LD mapping?
- Linkage resulted from recombination events in last 2-3 generations; LD from ancestral recombination
- Linkage measures co-segregation in pedigree; LD measures co-segregation in a population
- Linkage detected for markers close to disease; LD detected for markers even closer
