Association Studies and Linkage Disequilibrium

Flashcards covering key concepts related to association studies and linkage disequilibrium.

What is genetic association?

The occurrence of two or more traits in a population of individuals more often than explained by chance, where at least one trait is genetic.

What is the focus of Association Studies?

A correlation between a specific variant and disease status or quantitative trait in a population.

What are the stages in conducting an association study?

Power or sample size calculations, collection of samples and DNA, SNP selection, genotyping, analysis and interpretation.

Give an example to illustrate Association Studies

HLA-DR4 is found in 36% of the general UK population but in 78% of people with rheumatoid arthritis.

Why are association studies needed?

Susceptibility factors for complex traits are relatively weak, heterogeneous or both.

What measures are available to assess relative risk in disease susceptibility?

Likelihood ratio and the odds ratio.

What does the likelihood ratio measure?

The likelihood that a person with the susceptibility factor will develop the disease, compared to the general population.

What is a key advantage of using the odds ratio in case-control studies?

It can be calculated directly from the results of the study, without needing wider population data.

What does an odds ratio (OR) > 1 indicate in association studies?

AB is positively associated with disease.

How is Linkage Disequilibrium (LD) used?

Measures correlation between loci

What does Odds Ratio (OR) measure and how is it used with LD?

Strength of association between allele/haplotype and disease; used in case-control studies to infer LD indirectly.

What does Likelihood Ratio (LR) measure and how is it used with LD?

How much more likely data are under one model vs another; used in LD testing and model selection.

What are possible causes of population association, not all of which are genetic?

Direct causation, epistatic effect, population stratification, Type I error, linkage disequilibrium (LD)

How does linkage disequilibrium (LD) contribute to associations in disease studies?

Disease-associated allele marks an ancestral chromosome segment carrying a sequence variant causing susceptibility.

What is linkage disequilibrium (LD)?

Particular combinations of alleles at closely linked loci occur more (or less) often than the individual allele frequencies would predict.

Why are SNPs used when genotyped for a series of linked polymorphic markers?

They are sufficiently abundant, have a lower mutation rate than microsatellites, and are easy to genotype on a large scale.

What are the advantages of association studies compared to linkage analysis?

Easier to conduct than linkage analysis, because neither multi-case families nor special family structures are needed

What is a key limitation of association studies?

Depends on linkage disequilibrium, which is a very short-range phenomenon in comparison with linkage.

What is the HapMap project?

Study of linkage disequilibrium across the human genome

What is involved in the Statistical Analysis for Association Studies

Statistical analysis: Chi-squared test, Software packages: UNPHASED, WHAP, FBAT, Merlin, PLINK, ParseCNV and Golden Helix's SNP & Variation Suite

Practically performing an Association study involves

Association studies can be designed in many different ways

What is the first step in practically performing an association study?

Choose a particular disease that has a genetic basis regarding onset, progression, or drug response.

What is step 3 in performing association study?

Choose specific genes and specific SNPs using databases like dbSNP, NCBI, dbVar, and ClinVar.

What is step 4 in practically performing an Association study?

Collect samples from cases and controls, perform DNA polymorphism screening.

What happens in Stage-1 of Association studies

The full set of SNPs is genotyped in a fraction of samples, and a liberal p-value threshold is used to identify a subset of SNPs with putative associations.

What happens in the Stage-2 and Stage-3 of Association studies

The SNPs identified from the first stage are re-tested in populations that are larger or of a similar size to distinguish true-positive associations.