Statistical methods for genetic association studies

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Statistical methods forgenetic association
studies
http//www.stats.gla.ac.uk/paulj/assoc_study_stat
s.ppt
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• A tutorial on statistical methods for population
  association studies
• David Balding
• Nature Reviews Genetics (2006) 7781-791

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(No Transcript)
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Recombination
X/x unobserved causative mutation A/a distant
marker B/b linked marker
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Approaches to finding disease genes

• Population-based association study
• unrelated subjects
• Family-based association study
• nuclear families
• Admixture mapping
• recently admixed population
• Linkage mapping
• large pedigrees

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Types of population association study

• Candidate causative polymorphism
• SNP (single nucleotide polymorphism), deletion,
  duplication
• Candidate causative gene (5-50 marker SNPs)
• evidence from linkage study or function
• Candidate causative region (100s of marker SNPs)
• evidence from linkage study
• Genome-wide (gt300,000 marker SNPs)
• no prior evidence required

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Common disease common variant (CDCV) hypothesis
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Preliminary analysis data quality

• Assuming mating is random and the population is
  large, HWE genotype frequencies will apply
• Allele frequencies
• P(X) p
• P(x) q
• HWE genotype frequencies
• P(XX) p2
• P(Xx) 2pq
• P(xx) q2
• Useful data quality check
• chi-squared or exact test
• log QQ plot
• But can discard causative mutations

p q
p p2 pq
q pq q2
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Log QQ plot
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Preliminary analysis dealing with missing data

• Imputation
• various methods maximum likelihood probalistic
  hot-deck regression modelling
• test for independence of missingness and
  case-control status

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Choice of inheritance model
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Choice of inheritance model
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Choice of inheritance model
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Tests of association single SNP

• Case-control
• Treat genotype as factor with 3 levels, perform
  2x3 goodness-of-fit test. Loses power if effect
  is additive
• Count alleles rather than individuals, perform
  2x2 goodness-of-fit test. Out of favour because
• sensitive to deviation from HWE
• risk estimates not interpretable

Major allele homozygote (0) Heterozygote (1) Minor allele homozygote (2)
Case
Control
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Tests of association single SNP

• Case-control
• Cochran-Armitage test
• loses power if additivity assumption wrong

Cochran-Armitage test
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Tests of association single SNP

• Case-control
• Armitage or goodness-of-fit? Depends on
• Prior knowledge of inheritance (additive,
  dominant, etc)
• Genotype frequencies, e.g. use Armitage test when
  minor allele is rare, goodness-of-fit test
  otherwise

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Tests of association single SNP

• Case-control
• Logistic regression
• Easily incorporates inheritance model (additive,
  dominant, etc)
• But assumes phenotype is outcome variable not
  genotype, so easier to justify for prospective
  studies

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Tests of association single SNP

• Continuous outcome
• Linear regression
• Ordered categorical outcomes
• Multinomial regression

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Problems population stratification
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Correcting for population stratification

• Genomic control
• Genotype null SNPs and use to calculate
  background inflation in test statistic due to
  population stratification
• Limited to simple single-SNP analyses
• Can over- or under-correct
• Other approaches using null SNPs
• Regression, principal components analysis, model
  underlying demography

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Problems multiple testing

• Bonferroni correction
• conservative when SNPs are linked
• Permutation
• computationally demanding
• False discovery rate
• Bayesian approaches

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Tests of association multiple SNPs

• Advantages
• Many SNPs may be linked to a gene, but
  individually may not have a significant effect
• Interactions between SNPs can be modelled
• Tag SNPs can reduce testing of redundant linked
  SNPs
• Methods
• Linear regression, logistic regression
• Armitage test
• Haplotype-based methods
• Natural interpretation
• But power reduced due to multiple alleles

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Haplotypes
Nature Genetics  37, 915 - 916 (2005)
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Inferring haplotype phase


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Inferring haplotype phase






?
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Inferring haplotype phase






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Inferring haplotype phase






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Inferring haplotype phase

• Methods software
• PHASE, FASTPHASE
• EH
• FBAT
• HAPLOTYPER
• EM-DECODER
• PLEM
• HAP
• HAPLORE
• Haplo.stat
• SNPEM
• PEDPHASE
• SNPHAP
• TDTHAP

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Inferring haplotype phase

• Phase cases and controls separately or pooled?
• Separating can give inflated type I error
• Pooling can reduce power