Genome wide association studies
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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


Mike snyder s ipop reveals diabetes

Mike Snyder’s iPOP Reveals Diabetes


Genome wide association studies

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


From genotyping to allele counts

From Genotyping to Allele Counts


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?


Gwas pvalues

GWAS Pvalues


Genome wide association studies

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.


Genome wide association studies

Manolio et al., Clin Invest 2008


Pitfalls of association studies

Pitfalls of Association Studies

  • Not very predictive


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


Genotyping principal components pcs can model population stratification

Genotyping Principal Components (PCs) Can Model Population Stratification

  • Li et al., Science 2008


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


Detection power of gwas

Detection Power of GWAS


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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