Association Analysis

Question 1

What is genetic association?

Answer 1

→ The presence of a variant allele at a higher frequency in unrelated subjects with a particular disease cases compared to those that do not have the disease

Question 2

What is a haplotype?

Answer 2

→ The order of alleles along a chromosome

Question 3

What is an allele?

Answer 3

→ One form of a variant in the genome

Question 4

What is a locus?

Answer 4

→ a position in the genome

Question 5

What is a genotype?

Answer 5

→ both alleles at a locus

Question 6

What is a case control study?

Answer 6

→ Case group who all have the disease

→ Controls that match the people with the disease for non-disease traits such as ; age, location, ethnicity

Question 7

What are the requirements for a good case control study?

Answer 7

→ Large numbers of well defined cases
→ Equal numbers of matched controls

→ Reliable genotyping technology
→ Standard statistical analysis

Question 8

What extra step do you need to do when you find a positive association?

Answer 8

→ Replicate

→ To prove that it is not by chance

Question 9

What are characteristics of an ideal genetic marker?

Answer 9

→ Polymorphic
→ Randomly distributed across the genome

→ Fixed location in the genome
→ Frequent in genome
→ Frequent in population
→ Stable with time
→ Easy to assay (genotype)

Question 10

How often are SNPs found in the genome?

Answer 10

→ 1 in every 300 nucleotides

Question 11

How many SNPs have been identified in the genome?

Answer 11

→ 12 million

Question 12

How are SNPs formed?

Answer 12

→ The repair mechanism inserts a matching nucleotide to the wrong base so it is different from the original pair

Question 13

What is the effect of SNPs found in the coding region?

Answer 13

→ Coding region
→ no amino acid change

→ amino acid change
→ new stop codon

Question 14

Where can SNPs be found in the non coding region and what is the effect?

Answer 14

→ Promoter - mRNA and protein level changed
→ Terminator - mRNA and protein level changed

→ Splice site - altered mRNA, altered protein

Question 15

What do the major and minor allele frequency add up to?

Answer 15

→ 1

Question 16

What is a GWAS?

Answer 16

→ genome wide association study

→ association between disease and alleles of each marker - chi squared test

Question 17

How is GWAS data represented?

Answer 17

→ a single graph called the Manhattan plot

Question 18

What are the axes on a Manhattan plot?

Answer 18

→ X axis is the position of the SNP on the chromosome

→ Y axis is the -log10 (P value) of the association - done by chi squared

Question 19

What does a peak on the Manhattan plot signify?

Answer 19

→ The peak does not identify the gene causing the disease

→ It identifies the genomic regions associated with disease and is smaller than 100kb

Question 20

Why is the scale -log10 on the manhattan plot?

Answer 20

→ The probability of a result being due to chance is very high because there are so many samples

→To produce a linear graph

Question 21

What is meta analysis?

Answer 21

→ Allows the statistical combination of results from multiple studies

Increases statistical power

Question 22

What % of body shape is genetically determined in twin studies?

Answer 22

→ 70-80%

Question 23

What is the gene associated with obesity?

Answer 23

→ FTO

Question 24

What is the minimum accepted p-value for GWA significance?

Answer 24

p<5x10-8

Question 25

What is the problem with GWAS?

Answer 25

→contribution to the genetic component of disease is estimated to be low (<5%)

Question 26

Why is GWAS contribution to genetic diseases low?

Answer 26

→Many common SNPs of very small effect
→Rare SNPs
→Copy Number Variation
→Epigenetic variation

Question 27

In what two ways can you combine smaller studies?

Answer 27

→Pre-experiment – Consortium

→Post-experiment – Meta-analysis

Question 28

What is the rs number?

Answer 28

a unique identifier given to each SNP

Question 29

What does Association mean?

Answer 29

<100kb from a causal variant