Question 1

Which of the following best explains why genome-wide association studies (GWASs) have limited predictive value for most complex diseases?

Accepted Answer

GWASs typically identify variants with small effect sizes, which explain only a small proportion of trait heritability.

Question 2

A GWAS identifies a SNP with an odds ratio (OR) of 1.2 for a common disease. What does this imply about the SNP's utility in clinical risk prediction?

Accepted Answer

The SNP has limited utility because an OR of 1.2 is too small to significantly improve risk prediction over clinical factors.

Question 3

Why do GWAS signals often fall in non-coding regions, and what is the current hypothesis about their function?

Accepted Answer

They are often located in enhancers or regulatory elements that influence gene expression.

Question 4

Which of the following is a key limitation of GWAS arrays in detecting genetic variation?

Accepted Answer

They are less effective at capturing structural variation such as insertions, deletions, and copy number variants.

Question 5

In the context of GWAS, what does the area under the receiver operator characteristic (ROC) curve (AUC) represent?

Accepted Answer

The ability of a measure to discriminate between those with and without disease.

Question 6

A patient is prescribed simvastatin. Genetic testing reveals they are homozygous for the SLCO1B1 rs4149056 C allele. What is the clinical implication?

Accepted Answer

They are at high risk for statin-induced myopathy and may require dose reduction or alternative therapy.

Question 7

Which of the following scenarios best illustrates a promising clinical application of GWAS findings?

Accepted Answer

Using a genetic risk score to target autoantibody screening for type 1 diabetes in high-risk individuals.

Question 8

Why is the predictive value of genetic models often lower when applied to populations different from the one in which they were developed?

Accepted Answer

Differences in genotype frequencies, effect sizes, and disease incidence between populations affect model performance.

Question 9

A GWAS identifies a common SNP in the ITPA gene that protects against ribavirin-induced anemia. What is the mechanism?

Accepted Answer

ITPA deficiency leads to accumulation of ITP, which substitutes for GTP in ATP biosynthesis, reducing hemolysis.

Question 10

Which of the following is a reason why GWAS findings for type 1 diabetes are particularly clinically useful compared to other complex diseases?

Accepted Answer

Identified loci explain a large proportion of familial risk, and predictive models have high AUC values.

Question 11

A patient with young-adult-onset diabetes is found to have low C-reactive protein (CRP) levels and a mutation in HNF1A. What is the clinical significance?

Accepted Answer

They likely have HNF1A-MODY, which may be better managed with sulphonylureas rather than insulin.

Question 12

Which of the following best describes linkage disequilibrium (LD) in the context of GWAS?

Accepted Answer

LD allows a single 'tag' SNP to serve as a proxy for much of the surrounding genetic variation.

Question 13

Which of the following is a challenge in translating GWAS findings into clinical care?

Accepted Answer

The need for rapid, low-cost genotyping and integration with clinical decision support tools.

Question 14

A ROC curve for a genetic risk model has an area under the curve (AUC) of 0.5. What does this indicate?

Accepted Answer

The model provides no discrimination between those with and without the condition.

Question 15

Which of the following is a potential benefit of using GWAS-defined genotype scores in cardiovascular risk assessment?

Accepted Answer

They can reclassify individuals from intermediate to low or high risk, improving clinical decision making.

Question 16

Which of the following best describes the role of pharmacogenetic variants identified by GWAS in drug development?

Accepted Answer

They can identify loss-of-function variants that protect against drug toxicity, suggesting new therapeutic targets.

Question 17

A GWAS identifies a SNP in SLCO1B1 associated with both statin-induced myopathy and methotrexate toxicity. What does this suggest about the gene's function?

Accepted Answer

SLCO1B1 encodes a transporter involved in hepatic drug uptake, affecting the pharmacokinetics of multiple drugs.

Question 18

Which of the following is a reason why GWAS findings are more likely to be clinically translatable when effect sizes are large?

Accepted Answer

Large effect sizes make it easier to identify associations that have meaningful clinical impact.

Genome-Wide Association Studies (GWAS): Clinical Applications and Limitations

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