Genome-Wide Association Studies Overview
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What is the primary goal of Genome Wide Association Studies (GWAS)?

  • To analyze the effects of environmental factors on genetics
  • To identify rare genetic variants
  • To map the entire human genome
  • To identify common variants associated with diseases (correct)

    • Which of the following best describes the concept of 'missing heritability' in GWAS?

  • The inability to measure the effect of all environmental factors
  • The genetic information that does not get passed to offspring
  • The observed heritability of traits that cannot be fully accounted for by identified variants (correct)
  • The genetic variants that have no impact on phenotype

    • Which hypothesis suggests that common diseases are influenced by common genetic variants?

  • Environmental interaction hypothesis
  • Common disease-common variant hypothesis (correct)
  • Common disease-rare variant hypothesis
  • Polygenic risk hypothesis

    • What does the term 'linkage disequilibrium' (LD) refer to in the context of GWAS?

    <p>The sharing of ancestral chromosome segments due to common ancestry</p> Signup and view all the answers

    Which of the following statements is true regarding the sharing of ancestral chromosome segments?

    <p>The extent of sharing is greatest in siblings and decreases with distance from the common ancestor.</p> Signup and view all the answers

    What information does a Q-Q plot provide in a GWAS?

    <p>Distribution of observed test statistics against expected values</p> Signup and view all the answers

    What color represents previously discovered loci in a Manhattan plot?

    <p>Red</p> Signup and view all the answers

    What correction method is used to adjust p-values in GWAS when many tests are performed?

    <p>Bonferroni Correction</p> Signup and view all the answers

    What is the interpretation of an odds ratio (OR) greater than 1 in GWAS?

    <p>SNP increases the odds of having the trait</p> Signup and view all the answers

    In the allele counting method for colorectal cancer association, which allele is considered the risk allele for rs6983267?

    <p>C allele</p> Signup and view all the answers

    What is the threshold p-value for significance in the context of a GWAS?

    <p>5 x 10^-8</p> Signup and view all the answers

    What type of studies typically use chi-squared tests to compare genotype counts?

    <p>Case-control studies</p> Signup and view all the answers

    What does an odds ratio (OR) equal to 1 indicate?

    <p>SNP has no association with the trait</p> Signup and view all the answers

    What do the 8 SNP loci at 5q31 reveal about haplotype diversity?

    <p>They suggest that defined blocks of limited haplotype diversity exist.</p> Signup and view all the answers

    How many possible haplotypes can arise from genotyping 8 SNP loci?

    <p>256</p> Signup and view all the answers

    What is the purpose of tagging SNPs in a GWAS?

    <p>To differentiate and represent common haplotypes at each locus.</p> Signup and view all the answers

    What do adjacent haplotype blocks at 5q31 signify?

    <p>They demonstrate variations in haplotype switching across populations.</p> Signup and view all the answers

    Which step in a GWAS involves comparing allele frequencies between groups?

    <p>Genotyping tagged SNPs.</p> Signup and view all the answers

    What is the significance of the red asterisk in the context of the discussed mutation?

    <p>It indicates a newly emergent mutation.</p> Signup and view all the answers

    Which technological advance was pivotal in enabling Genome-Wide Association Studies (GWAS)?

    <p>International HapMap project.</p> Signup and view all the answers

    What does the presence of a higher frequency of allele 2 in descendants indicate?

    <p>It implies an increased chance of disease susceptibility.</p> Signup and view all the answers

    What percentage of genetic predisposition to multiple sclerosis can currently be explained by validated susceptibility alleles?

    <p>39%</p> Signup and view all the answers

    Which of the following best describes the common disease – common variant hypothesis?

    <p>Multiple common variants at different loci increase disease risk.</p> Signup and view all the answers

    How many individual genotypes are extracted in the described GWAS setup?

    <p>1000 cases and 1000 controls.</p> Signup and view all the answers

    What is the purpose of calculating which SNPs are more frequent in cases than controls?

    <p>To determine the role of SNPs in disease susceptibility.</p> Signup and view all the answers

    What is a significant limitation of GWAS when it comes to identifying disease variants?

    <p>Identified variants contribute moderately to genetic variance.</p> Signup and view all the answers

    Which genetic mechanisms are primarily involved in the common disease – rare variant hypothesis?

    <p>Rare mutations of strong effect not in common haplotypes.</p> Signup and view all the answers

    What do haplotype blocks help to define in genomic studies?

    <p>Ancestral chromosome segments.</p> Signup and view all the answers

    What is a common characteristic of complex diseases in the context of GWAS?

    <p>They are often assumed to be caused by common variants.</p> Signup and view all the answers

    How many genome-wide associations related to multiple sclerosis were identified outside of the MHC region?

    <p>200</p> Signup and view all the answers

    Which method is currently used for high-throughput genotyping in genomic studies?

    <p>Next Generation Sequencing (NGS).</p> Signup and view all the answers

    What is typically true about common variants in the context of genetic susceptibility to diseases?

    <p>They generally represent susceptibility factors with weak effects.</p> Signup and view all the answers

    Why do common disease variants identified by GWAS often show weak effects?

    <p>They represent mild missense mutations or changes.</p> Signup and view all the answers

    What factor contributes to the concept of missing heritability in complex diseases?

    <p>A small proportion of genetic variance explained by identified variants.</p> Signup and view all the answers

    Study Notes

    Genome-Wide Association Studies (GWAS)

    • GWAS aim to identify common variants that contribute to complex diseases
    • Technological advances: High-throughput genotyping using microarrays & the International HapMap project
    • Haplotype blocks: Defined segments of limited haplotype diversity
      • Suggest that our DNA is composed of these blocks
      • In European populations, just two haplotypes account for most of the chromosomes in an 84kb region
    • GWAS steps:
      • Selection of tagging SNPs: Representative SNPs are selected using HapMap data. These SNPs differentiate common haplotypes at each locus.
      • Genotyping: Tagged SNPs are genotyped in cases and controls using microarrays
      • Allele frequency comparison: Allele frequencies for each SNP are compared between cases and controls
      • Identifying associated SNPs: SNPs statistically associated with the disease are then genotyped in a second independent cohort for validation.
    • Visualising GWAS data:
      • Manhattan Plots:
        • Display p-values for each SNP across the genome
        • SNPs with significant associations are highlighted
      • Quantile-Quantile (Q-Q) plots:
        • Compares the distribution of observed test statistics to expected values under the null hypothesis of no association
        • Used to identify potential population stratification or other biases
    • Odds Ratio (OR):
      • Measures the strength of association between a SNP and a disease
      • OR > 1: The SNP is associated with higher odds of the disease
      • OR < 1: The SNP is associated with lower odds of the disease
      • OR = 1: No association
    • Limitations of GWAS:
      • Common variants identified by GWAS often have weak effects
      • GWAS data only explain a small proportion of the genetic variance of complex diseases - referred to as missing heritability
    • Hypotheses explaining complex disease inheritance:
      • Common Disease - Common Variant Hypothesis:
        • Common variants with low penetrance contribute to disease susceptibility
        • Explains the steep decrease in disease risk in relatives of probands
        • Common variants are expected to be of ancient origin
      • Common Disease - Rare Variant Hypothesis:
        • Multiple rare variants with differing effects contribute to disease susceptibility
        • Some rare variants may have strong penetrance
        • Rare variants are expected to be of more recent origin
    • Missing heritability:
      • The difference between the estimated genetic contribution to a complex disease based on GWAS and the actual observed heritability
      • Attributed to factors like: rare variants, gene-gene interactions, gene-environment interactions, and complex gene regulation
    • Multiple Sclerosis (MS):
      • GWAS have identified over 200 genetic loci associated with MS
      • Most identified variants are in immune pathways
      • The MHC region is a major contributor to MS risk

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    Lecture 5 GWAS PDF

    Description

    This quiz focuses on Genome-Wide Association Studies (GWAS) and their role in identifying genetic variants linked to complex diseases. It discusses the technological advances that enable GWAS, the concept of haplotype blocks, and the step-by-step process involved in conducting a GWAS. Test your knowledge on these fundamental genetic research methods!

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