Association Analysis

Question 1

Define the term “Genetic Association”

Answer 1

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Question 2

Describe how a genetic association study is conducted

Answer 2

• cases and controls (well matched for risk factors)
• measure for genetic loci of interest: what allele is common in all cases which is not present in controls?

Question 3

Describe an ideal genetic marker and how SNPs fit this description

Answer 3

genetic markers:
- polymorphic
- random distribution across genome
- frequent and fixed position
- stable with time
easy to genotype

SNPs:
- located 1 in every 3000 nucleotides
- 12 million recorded in database
- generated by mismatch repair during meiosis
- could be a MAF (minor sequency allele)
location in ‘coding region’: synonymous change, amino acid change = non-synonymous, new stop codon = nonsense
- location in exon : promoter, terminator, splice site / intergenic region

Question 4

Describe the principles of a genome-wide association study (GWAS)

Answer 4

GWAS:
- recruitment of large sets of cases and controls
-using SNP microarrays as genotype markers across the genome
- chi squared test: statistical significance of p-value (above 5%) show more than 95% probability the observed results are NOT due to chance

Question 5

Describe and interpret a Manhattan plot

Answer 5

Manhattan plot:
- y axis -log10(p-value) / chromosomes (x- axis)
- alternating colours for each chromosomes
- higher = different shaded peaks with SNP association due to linkage disequilibrium
- sky scraper = peaks

Question 6

Describe and interpret a regional association plot

Answer 6

regional association= lines up asosicated SNPs against gene reigons along chromosome (zooming into the sky-scraper peaks) the higest log(p-val) shows strongest loci association to causal variant

Question 7

Describe meta-analysis and how it is used in genetic studies

Answer 7

meta analysis = implementing/combining loads of GWAS studies and adding it to their data = combining data from multiple small studies

Question 8

Describe the known problems with GWAS

Answer 8

• 5% contribution to disease
• no CNV covered
• common SNPs only

Question 9

Give an example of how GWAS has identified susceptibility variants in genes in a common disease

Answer 9

• plot manhattan
• observe peaks
• region association
• share/combine studies
  eg: obesity FTO

Question 10

Describe the relationship between genetic association and linkage disequilibrium

Answer 10

disequilibrium