47 Questions
What is the term for a unique set of alleles that always occur together within a linkage block?
Haplotype
How are haplotypes identified within linkage blocks?
By genotyping single nucleotide polymorphisms (SNPs)
What is the term for the association of alleles from different loci because they are on the same linkage block?
Linkage disequilibrium
In the multiplicative inheritance model, how is disease risk affected by each additional 'A' allele?
Disease risk is increased $\gamma$-fold with each additional 'A' allele
What is the goal of Genome Wide Association Studies (GWAS)?
To map causal mutation(s) to chromosomes
What is the coefficient of Linkage Disequilibrium (LD), D, defined as?
D = pAB – pApB
What does Linkage Disequilibrium (LD) measure?
The extent to which two alleles on different loci are associated together
What does strong Linkage Disequilibrium (LD) on chromosomes indicate?
The loci are very close to each other on the chromosome
What are haplotype blocks?
Segments of chromosomes with strong LD
What is the difference between the frequency of gametes carrying the pair of alleles A and B at two loci (pAB) and the product of the frequencies of those alleles (pA and pB) called?
Linkage Disequilibrium (LD)
What is the ramification of two loci being very close to each other on a chromosome?
Their alleles will nearly always be inherited together
What is the main rationale for considering missense mutations as causal mutations?
They disrupt proteins and are often the cause of severe, rare, Mendelian inherited diseases
What is the main challenge in understanding complex diseases with numerous subtle mutations?
Understanding the subtle changes in protein or expression caused by the mutations
What did Hirschorn & Daly suggest as the most comprehensive approach towards understanding complex diseases?
Complete genome resequencing in a large population of cases and controls
What did Nik-Zainal et al. analyze to advance understanding of driver mutations in breast cancer?
Whole-genome sequences of 560 breast cancer cases
What concept explains how phenotypes are associated with genotypes?
Genotype-Phenotype Association
What is the main purpose of a Bonferroni correction in GWAS studies?
To account for multiple testing and reduce the chance of false positives
What is the key challenge in performing a complete genome resequencing in a large population of cases and controls?
Lack of feasibility
What is the purpose of haplotype blocks in GWAS?
To find genes affecting phenotypes and enable large-scale GWAS
What is the main reason for including low frequency SNPs (<5%) in human SNP chips for GWAS?
To capture genetic variants that may have a significant impact on complex traits
What is the purpose of Bonferroni correction in GWAS?
To correct for multiple-hypothesis testing in GWAS
What can lead to biased results in GWAS if not accounted for?
Population stratification due to admixture
What is the purpose of a multistage approach in GWAS?
To reduce genotyping cost while maintaining power
What is the measure of effect size and strength of association in GWAS?
Odds ratio
What is the term for the measure of effect size and strength of association in GWAS?
Relative Risk
In the context of inheritance patterns, what does 'penetrance' refer to?
The risk of disease in a given individual
What is the main reason for including low frequency SNPs (<5%) in human SNP chips for GWAS?
To identify causal genes in LD with significant SNPs in the region
What is the coefficient of Linkage Disequilibrium (LD), D, defined as?
The difference between the frequency of gametes carrying the pair of alleles A and B at two loci (pAB) and the product of the frequencies of those alleles (pA and pB)
What does strong Linkage Disequilibrium (LD) on chromosomes indicate?
High likelihood of alleles occurring together on a chromosome
Where does Linkage Disequilibrium (LD) come from?
Closeness of loci on a chromosome, leading to a decreased likelihood of recombination
What is the purpose of haplotype blocks in GWAS?
To find genes affecting phenotypes and enable large-scale GWAS
What can lead to biased results in GWAS if not accounted for?
Population stratification and missing data
What is the measure of effect size and strength of association in GWAS?
Odds ratio
What is the main rationale for considering missense mutations as causal mutations?
They often disrupt proteins and are more often the case in severe, rare, Mendelian inherited diseases
What is the coefficient of Linkage Disequilibrium (LD), D, defined as?
A measure of the non-random association of alleles at two or more loci
What is the purpose of Bonferroni correction in GWAS?
To adjust for multiple hypothesis testing and reduce the likelihood of false positives
What did Nik-Zainal et al. analyze to advance understanding of driver mutations in breast cancer?
Whole-genome sequences of 560 breast cancers
What does strong Linkage Disequilibrium (LD) on chromosomes indicate?
Non-random association of alleles at two or more loci
What is the coefficient of Linkage Disequilibrium (LD), D, defined as?
A measure of the difference between the frequency of gametes carrying the pair of alleles at two loci and the product of the frequencies of those alleles
What is the main rationale for considering missense mutations as causal mutations?
They have a larger impact on protein function than non-coding variants
What is the purpose of Bonferroni correction in GWAS studies?
To account for multiple testing and reduce the likelihood of false positives
Where does Linkage Disequilibrium (LD) come from?
It is introduced through recombination and genetic linkage
What is the measure of effect size and strength of association in GWAS?
Odds ratio
What is the key challenge in performing a complete genome resequencing in a large population of cases and controls?
Managing the vast amount of genetic data generated
What is the purpose of haplotype blocks in GWAS?
To capture and analyze genetic variation across the genome
What is the term for the association of alleles from different loci because they are on the same linkage block?
Linkage Disequilibrium
What did Nik-Zainal et al. analyze to advance understanding of driver mutations in breast cancer?
Whole-genome sequences of breast cancers
Study Notes
Genome Wide Association Studies (GWAS) in Medical News
- GWAS studies focus on the cumulative action of many genes and the environment for complex phenotypes and diseases
- GWAS surveys most of the genome for causal genetic variants and can be applied to quantitative and complex traits
- Haplotype blocks are used to find genes affecting phenotypes and enable large-scale GWAS
- Human SNP chips can assay >1 million SNPs and need to include low frequency SNPs (1-5%)
- Correcting for multiple-hypothesis testing is necessary in GWAS due to the large number of independent tests
- Odds ratio is a measure of effect size and strength of association in GWAS
- False positives in GWAS can result from random effects, systematic bias, population stratification, and missing data
- Population stratification due to admixture can lead to biased results in GWAS if not accounted for
- GWAS requires genotyping of thousands of individuals to have power, and a multistage approach can reduce genotyping cost while maintaining power
- Bonferroni correction is punitively conservative and permutation testing can find a more appropriate p-value threshold
- GWAS studies need to repeat with another set of samples and a subset can be retested with a denser SNP assay
- Critical to take population structure into account when doing GWAS to avoid biased results due to population stratification
Genome Wide Association Studies (GWAS) in Medical News
- GWAS studies focus on the cumulative action of many genes and the environment for complex phenotypes and diseases
- GWAS surveys most of the genome for causal genetic variants and can be applied to quantitative and complex traits
- Haplotype blocks are used to find genes affecting phenotypes and enable large-scale GWAS
- Human SNP chips can assay >1 million SNPs and need to include low frequency SNPs (1-5%)
- Correcting for multiple-hypothesis testing is necessary in GWAS due to the large number of independent tests
- Odds ratio is a measure of effect size and strength of association in GWAS
- False positives in GWAS can result from random effects, systematic bias, population stratification, and missing data
- Population stratification due to admixture can lead to biased results in GWAS if not accounted for
- GWAS requires genotyping of thousands of individuals to have power, and a multistage approach can reduce genotyping cost while maintaining power
- Bonferroni correction is punitively conservative and permutation testing can find a more appropriate p-value threshold
- GWAS studies need to repeat with another set of samples and a subset can be retested with a denser SNP assay
- Critical to take population structure into account when doing GWAS to avoid biased results due to population stratification
Test your knowledge of Genome Wide Association Studies (GWAS) with this quiz! Learn about the application of GWAS in understanding complex phenotypes and diseases, the use of haplotype blocks, SNP chips, and the necessity of correcting for multiple-hypothesis testing. Explore the challenges and considerations in GWAS, including population stratification and strategies to increase power while reducing genotyping cost.
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