Genome Wide Association Studies (GWAS)

Question 1

What technological advances allowed GWAS?

Answer 1

1. International HapMap project delivering millions of mapped SNPs
2. Extension of microarray technology allowed automated genotyping of huge numbers of SNPs

Question 2

What are GWAS?

Answer 2

Genome wide association studies designed to identify common variants = assume common complex diseases caused by common variants. Using Case-control studies

Question 3

Why use SNPs over microarrays in GWAS?

Answer 3

• Microarrays only occur 1/50,000 compared to 1/1000 for SNPs
• SNPs may be less informative but have genotyping platforms

Question 4

What is the workflow of GWAS?

Answer 4

1. Using HapMap data, SNPs selected which tag the common haplotypes at each locus
2. Tagged SNPs genotyped in disease and control cases using microarray
3. Allele frequencies for each SNP compared in 2 groups
4. SNPs associated with disease are genotyped in replication test
5. Which associations are robust

Question 5

What are SNP chips?

Answer 5

Detect DNA variation via DNA chips, using known genomic sequence –> DNA hybridizes to chip

(key SNP tech)

Question 6

What is a whole genome high density chip?

Answer 6

Collection of 223 high density arrays containing more than 10 billion unique oligonucleotides

Question 7

How is GWAS data visualised?

Answer 7

On a Quantile-Quantile (Q-Q plot)

Question 8

How to find a gene in GWAS?

Answer 8

• Locate a chromosomal area associated with a particular syndrome
• screen hundreds of patients to find minimal region associated
• map all gene candidates
• check all candidates (try mutations, KO etc)
• study gene functions in the tissue and tumours

Question 9

What are the limitations of GWAS?

Answer 9

• common disease variants identified by GWAS have weak effects
• even cumulative contributions are small
• available GWAS data explain small portion of genetic variation of complex diseases = missing heritability

Question 10

What explains the missing heritability in GWAS?

Answer 10

• large numbers of common variants have weak effects
• rare variants have large effect
• gene-gene and gene-environment interactions (doesn’t take into account genetic interactions)

Question 11

What is the common variant hypothesis?

Answer 11

Different combinations of variants at multiple loci aggregate in specific individuals to increase disease risk. This explains the steep falling away of disease risk in relatives from ancestor with a common disease. Common variants are expected to be of ancient origin

Question 12

What is the rare variant hypothesis?

Answer 12

Rare variants as recent mutations, and so they are likely to have strong effects on an individual. But natural selection says that rare variants that are super deleterious aren’t likely to stay for more than a couple generations. So they wouldn’t appear on common haplotypes.

With complex diseases, there are subtypes which segregate according to Mendelian ratios where there are rare mutations with strong effects.

So rare variants with moderate effect may not be detected because they’re just below GWAS detection threshold