LD & HapMap

Question 1

Why have linkage studies got a low success rate in detecting complex traits?

Answer 1

Linkage studies have a low success rate in detecting complex traits. A greater statistical power is needed to detect them and therefore association studies are used.

Question 2

What are the potential causes of associations(ref the definition from previous lecture)?

Answer 2

Associations have several potential causes: direct causation, epistatic effects, popn. stratification, type 1 statistical errors, and linkage disequilibrium.

• Type 1 statistical errors – rejection of a true null hypothesis.
• Linkage disequilibrium – the nonrandom association between variants within a haplotype.

Question 3

Explain shared a certain chromosome segments.

Answer 3

• Two unrelated people inherit a disease susceptibility allele from a common ancestor.
• Repeated recombination during meioses over generations reduces size of the shared segment to a very small region and only alleles tightly linked to the susceptibility locus will still be shared.

Question 4

What is meant by decay of LD over time?

Answer 4

• In the absence of selection in a large, random mating popn., LD decreases exponentially each generation
• LD is reduced by a factor equal to the recombination rate between the two loci
• For example, the LD between two loci 10cM apart will be reduced by 10% per generation.

Question 5

LD is rare beyond… what might this information be used for?

Answer 5

• LD rare beyond 100 kb or so; and almost zero LD beyond 500 kb.
  
  • This information is used for mapping by association testing: If there is a strong association (a signature of LD), it means those markers must be within 100 kb of each other.

Question 6

Outline the international HapMap Project.

Answer 6

International HapMap Project launched in 2002 to provide a genome-wide database of common sequence variation.

• Unlike the earlier maps using RFLPs or microsatellites, HapMap is a high density map generated by using SNPs.

Question 7

Define direct association and indirect association.

Answer 7

• Direct association: SNP influencing a phenotype is directly
  genotyped in a study and found to be associated with trait
  
  • Sometimes referred to as the functional SNP
• Indirect association: a tag SNP in high LD with the functional
  SNP is genotyped and is associated with the phenotype
  
  • A significant association should not be assumed to be the
    causal variant – further studies need to map functional SNP

Question 8

Define Tag SNPs and how they are used(research).

Answer 8

• Suppose two SNPS have r2 = 1, they are completely correlated with each other.
• In a genome-wide association study would only need to genotype one of them (known as a tag SNP).

Question 9

What has since happened to the HapMap?

Answer 9

• The HapMap site was taken down in 2016.
• Buchanan et al (2012) states a possible decline in usage of HapMap over the previous 5 years as the 1,000 Genomes Project (launched in 2007 and final results published in 2015) established itself as a standard for population genetics and genomics.