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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

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genome wide association studies

Genome-Wide Association Studies

Xiaole Shirley Liu

Stat 115/215

association studies
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
slide5
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 studies1
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
Quality Control: SNP calls

Bad calls!

Good calls!

family based association studies tdt transmission disequilibrium test
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
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

test significant associations
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?
slide13
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
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.

pitfalls of association studies1
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
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
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
  • 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

causes for inconsistency
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
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
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
Missing Heritability?

Visccher, AJHG 2011

acknowledgement
Acknowledgement
  • Tim Niu
  • Kenneth Kidd, Judith Kidd and Glenys Thomson
  • Joel Hirschhorn
  • Greg Gibson & Spencer Muse
  • Jim Stankovich
  • Teri Manolio
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