Abbreviation:GWAS (genome-wide association study)
- •Recognize the newest techniques in biomedical research.
- •Describe how these techniques can be utilized and their limitations.
- •Describe the potential impact of these techniques.
Advantages and Limitations of GWAS
- •GWASs can identify new susceptibility regions without the need to know which variants may be relevant in advance (“hypothesis-free” approach).
- •Knowledge obtained from GWASs can be used to guide other types of experiments.
- •GWAS is a well-developed approach with many tools available for data analysis and interpretation of results.
- •GWAS is suitable for complex polygenic diseases, with many genes contributing only modestly to disease risk.
- •GWAS has the potential to guide development of precision (personalized) medicine and health care, especially when combined with other biomarkers.
- •GWAS needs a large sample size to achieve sufficient power (i.e., the multiple testing problem).
- •It is often not trivial to identify how variants affect biology.
Strategies for GWAS
|Properties||GWAS Array||Exome Array||Targeted Array|
|Number of markers||500,000 to 5,000,000||∼200,000 (can add GWAS content)||Vary (e.g., Immunochip and Metabochip, ∼200,000)|
|Regions of interest||Whole genome||Exome||Targeted|
|Allow imputation||Yes||No, if without GWAS content||Yes, but well-imputed markers are limited|
|Requires prior knowledge||For tagging||Exonic regions||Candidate regions|
|Variants to study||Common||Rare||Common/low allele frequency variants|
|Step||Description||Example Software Programs|
|Check genomic build|
|Sample genotyping rate|
|Check sex inconsistencies|
|Marker genotyping rate|
|Mapping probe to genome (to ensure unique mapping)|
|Remove monomorphic markers|
|Principal component analysis||EIGENSTRAT|
|Association||Single variant association/burden test for rare variants||PLINK-1.9|
|Pathway analysis||Identify enriched functions||INRICH|
|Candidate gene prioritization||Provide inference for the best candidate genes from associated loci||GRAIL|
Applications to interpret association results
Challenges and Future Directions
Multiple Choice Questions
- 1.Which of the following is NOT a type of array used for genotyping?
- 2.What is the typical range of values for imputed genotypes?
- A.0 to 1
- B.0 to 2
- C.–1 to 1
- D.0 to 100
- 3.Which of the following can be used to address population stratification?
- B.Genomic control
- C.Multiple testing
- 4.What P-value threshold is commonly used for genome-wide significance?
- A.5 × 10–4
- B.5 × 10–6
- C.5 × 10–8
- D.5 × 10–10
- 5.Which of the following is not a priority for GWAS research in skin disease?
- A.Increased sample size and integration across ethnicities
- B.Inferring the biological function of the disease loci identified
- C.Integrating information from clinical data for precision medicine
- D.Identifying differences in gene expression
Conflict of Interest
- Supplementary Table S1
- Teaching Slides
- Quiz and brief explanation of correct answers
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