Genome wide association studies
This presentation is the property of its rightful owner.
Sponsored Links
1 / 28

Genome-Wide Association Studies PowerPoint PPT Presentation


  • 145 Views
  • Uploaded on
  • Presentation posted in: General

Genome-Wide Association Studies. Xiaole Shirley Liu Stat 115/215. Association Studies. Association between genetic markers and phenotype Especially, find disease genes, SNP / haplotype markers, for susceptibility prediction and diagnosis

Download Presentation

Genome-Wide Association Studies

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Genome-Wide Association Studies

Xiaole Shirley Liu

Stat 115/215


Association Studies

  • Association between genetic markers and phenotype

  • Especially, find disease genes, SNP / haplotype markers, for susceptibility prediction and diagnosis

  • Influences individual decisions on life styles, prevention, screening, and treatment


Mike Snyder’s iPOP Reveals Diabetes


Warfarin and CYP2C9:

SNPs in Pharmacogenomics

  • Warfarin anticoagulant drug; CYP2C9 gene metabolizes warfarin.

  • A patient requiring low dosage warfarin compared to normal population, has an odd ratio of 6.21 for having  1 variant allele

  • Subgroup of patients who are poor metabolisers of warfarin are potentially at higher risk of bleeding

  • Aithal et al., 1999, Lancet.


Genome-Wide Association Studies

  • Two strategies:

    • Family-based association studies

    • Population-based case-control association studies

  • Quality Control

    • Unusual similarity between individual

    • Wrong sex

    • Trio has non-Mendelian inheritance

    • Genotyping quality


Quality Control: SNP calls

Bad calls!

Good calls!


Family-based Association StudiesTDT: Transmission Disequilibrium Test

  • Look at allele transmission in unrelated families and one affected child in each

  • Could also compare

    allele frequency

    between affected vs

    unaffected children

    in the same family

Like coin toss


Case Control Studies

  • SNP/haplotype marker frequency in sample of affected cases compared to that in age /sex /population-matched sample of unaffected controls

  • Size matters

Visscher, AJHG 2012


From Genotyping to Allele Counts


Test Significant Associations

  • Expected:

    • (24 + 278) * (24 + 86) / (24 + 278 + 86 + 296) = 49

    • (278+296) * (86+296) / (24 + 278 + 86 + 296) = 321

  • 2 = 27.5, 1df, p < 0.001

  • Multiple hypotheses testing?


GWAS Pvalues


GWAS Pvalues for Type II Diabetes

  • Bonferroni correction: most common, typically p < 10-7 or 10-8

  • Split samples to improve power

McCarthy et al, Nat Rev Genetics, 2008


Association of Alleles and Genotypes of rs1333049 (‘3049) with Myocardial Infarction

  • OR = 1, no disease association

  • OR > 1, allele increase risk of disease

  • OR < 1, allele decrease risk of disease

Samani N et al, N Engl J Med 2007; 357:443-453.


Manolio et al., Clin Invest 2008


Pitfalls of Association Studies

  • Not very predictive


Pitfalls of Association Studies

  • Not very predictive

  • Explain little heritability

  • Poor reproducibility

  • Poor penetrance (fraction of people with the marker who show the trait) and expressivity (severity of the effect)

  • Focus on common variation

  • Difficult when several genes affecting a quantitative trait

  • Many associated variants are not causal

  • No available intervention for many disease risks


Reproducibility of Association Studies

  • Most reported associations have not been consistently reproduced

  • Hirschhorn et al, Genetics in Medicine, 2002, review of association studies

    • 603 associations of polymorphisms and disease

    • 166 studied in at least three populations

    • Only 6 seen in > 75% studies


Cause for Inconsistency

  • What explains the lack of reproducibility?

  • False positives

    • Multiple hypothesis testing

    • Ethnic admixture/ stratification

  • False negatives

    • Lack of power for weak effects

  • Population differences

    • Variable LD with causal SNP

    • Population-specific modifiers


Population Stratification

  • Population stratification

    • e.g. some SNP unique to ethnic group

    • Need to make sure sample groups match

    • Hidden environmental structure

  • Two populations have different disease frequency, and different allele frequency.

  • Association picks up they are different populations!

Balding, Nature Reviews Genetics 2010


Genotyping Principal Components (PCs) Can Model Population Stratification

  • Li et al., Science 2008


Causes for Inconsistency

  • A sizable fraction (but less than half) of reported associations are likely correct

  • Genetic effects are generally modest

    • Beware the winner’s curse (auction theory)

    • In association studies, first positive report is equivalent to the winning bid

  • Large study sizes are

    needed to detect these

    reliably


Should we Believe Association Study Results?

  • Initial skepticism is warranted

  • Replication, especially with low p values, is encouraging

  • Large sample sizes are crucial

  • E.g. PPARg

    Pro12Ala &

    Diabetes


Replication, Replication, Replication

  • Meta-analysis of multiple studies to increase GWAS power

  • Combine data from different platforms / studies

  • Impute unmeasured or missing genotypes based on LD (e.g. HapMap haplotypes or 1000 Genomes)

  • Analyze all studies together to increase GWAS power


Missing Heritability?

Visccher, AJHG 2011


Detection Power of GWAS


Acknowledgement

  • Tim Niu

  • Kenneth Kidd, Judith Kidd and Glenys Thomson

  • Joel Hirschhorn

  • Greg Gibson & Spencer Muse

  • Jim Stankovich

  • Teri Manolio


  • Login