20.04.02 Association studies linkage v association linkage disequilibrium Flashcards
What is linkage analysis
Linking heritable traits to their chromosomal location.
What sort of disorders are suited to linkage analysis
-Highly penetrant monogenic disorders with mendelian inheritance.
What does linkage analysis require
Large, multi generational families.
What is linkage disequilibrium
Non-random association of alleles at two or more loci with a frequency greater than expected by chance.
What affects linkage disequilibrium
-Recombination: recombination between loci will gradually reduce LD.
-gene conversion
-selection: if there is a selective advantage to two alleles coexisiting then LD between alleles is more likely to be maintained.
-population structure: inbreeding, non-random mating alter expected allele distributions.
-new mutation: a high new mutation rate at a locus will make it hard to detect LD
-genetic drift: variation in the relative frequency of different genotypes in a small population, owing to the chance disappearance of particular genes as individuals die or do not reproduce.
-gene flow: transfer of genetic variation from one population to another.
population history: the older the population the shorter the segments of LD
What are association studies
- Compare cases to controls to identify association (statistical relationship) between a particular genotype/ haplotype and a genetic trait.
- Phenotype first approach
What is a GWAS
- Study of genetic variation across the whole genome “hypothesis free” to find association between a genetic marker and a trait.
- Phenotype first approach
- non-candidate driven
What 4 reasons can cause positive association
- Chance
- False linkage due to linkage disequilibrium between marker being studied and the true disease causing variant
- Bias resulting from population stratification
- True association. The genetic variant is important in disease causation
Disadvantages of GWAS
Does not test causality (further work required), prone to confounding variables, expensive (need large studies), missing heritability (identifies SNPs conferring only small effects)
Difference between linkage analysis and association analysis
Linkage looks at the relation between transmission of a locus and disease/trait within families. Whereas association analysis focuses on the relation between a specific allele and the disease/trait within a population
What is genetic linkage
Tendency of alleles that are closely located on a chromosome to be inherited together at meiosis. Genes with close loci are less likely to be separated onto different chromatids during recombination and are therefore genetically linked
What is the measure for likelihood of linkage
Logarithm of odds (lod) score
How is the lod score calculated
logarithm of the offs that the loci are linked divided by the odds that the loci are unlinked.
What is the lod score that signifies linkage
- Above 3
- i.e. 1000:1 in favour of linkage.
- Although significance is more like P=0.05 (5% chance of a false result), to account for concomitant increase in observing a positive lod score by chance when calculating linkage for multiple markers.
What is the lod score that supports evidence against linkage
Below -2
