Power to detect QTL Association

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Power to detect QTL Association

• Lon Cardon, Goncalo Abecasis
• University of Oxford
• Pak Sham, Shaun Purcell
• Institute of Psychiatry

F\lon\2001\Assocpower
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Association Power
In principle, power to detect association
involves same mechanics as linkage
We are interested in a significance
thresholds 1-b the probability of rejecting the
null when it is false N the number of individuals
required to do it
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Association Power
What are the important variables/parameters?

• Linkage
• Study design
• QTL effect size
• recombination fraction
• Association
• Study design
• QTL effect size
• Linkage disequilibrium
• allele frequencies of marker and QTL

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Association Power
In general, power is greater for association
than for linkage ie., fewer individuals
required, can detect smaller effects (h2 5
vs. 20) But, more markers may be tested,
false positives are (or may be) more relevant
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Effects of Linkage Disequilibrium

• Key question for positional cloning and
  candidate gene analysis
• LD expected to decay ? (1-q)G
• How far does it extend?
• Debates 3 kb 100 kb (Kruglyak rest of
  world).
• Population-specific (depends on ancestral
  demographics)
• Genomic region-specific (ie., depends on
  sequence features)
• Marker-specific (ie., depends on markers
  considered)

Variation dominates data
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Extent of Disequilibrium
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Pair-wise Disequilibrium
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Sensitivity to Disequilibrium
Power for ?0.001, h² .1, s² .3, ?
0. Average additive genetic value estimated at
the marker.
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Influence of Family Size
For robust tests (TDT, QTDT) class, Best
design includes parental genotypes, but they are
not mandatory As sibship size increases, missing
parental data becomes less important
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Effect of Family Structure
350 sib-pair parents 1400 genotypes 500
sib-pairs no parents 1000 genotypes 260
sib-trios no parents 780 genotypes
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Single Nucleotide Polymorphisms

• Common disease-common variant hypothesis Common
  diseases have been around for a long time.
  Alleles require a long time to become common
  (frequent) in the population. Common diseases are
  influenced by frequent alleles.
• The SNP Consortium (TSC)
• Collection of 10 pharmaceutical companies
  Wellcome Trust
• Identified gt 1 million SNPs across the genome
• public databases now have 1.5 million
  non-redundant SNPs (relatively few verified)
• SNPs detected on basis of common disease common
  variant hypothesis (caucasian, african american,
  asian)
• Should be preponderance of common alleles

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Extent of Disequilibrium
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Effects of Allele Frequency
Key question is not just frequency of QTL, but
frequency of marker in LD with it More important
that marker-QTL allele frequencies are the same
than that QTL is common i.e., CD-CV hypothesis
not as relevant as SNP map
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Trios For Genome-Wide Scan
ls 1.5, a 5 x 10-8, Spielman TDT
(Müller-Myhsok and Abel, 1997)
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Effect of Allele Frequencies
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Phenotypic Selection

• Efficiency gains for genotyping
• Well characterized for linkage mapping ...
• ... Association mapping gaining prominence
• Selection tresholds
• A priori versus Post hoc
• Common variant hypothesis
• Effect of allele frequency

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Selection Strategies

• Selection based on one tail
• Affected Proband, Affected Pairs
• Selection from either tail
• Extreme Proband
• Concordant Pairs
• Discordant Pairs
• Discordant and Concordant

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Selection Tresholds

• Hard definition
• A priori
• Treshold defined before sample collection
• Eg, pairs with both sibs in top decile
• Adaptable selection
• Post hoc
• Tresholds defined after sample collection
• Eg, subselection from large twin registries

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Intensity of a priori selection
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Selection of Triads
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(No Transcript)
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Post hoc Selection
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Effect of Allele Frequencies
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Effect of Selection
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Summary

• Power for association generally greater than
  linkage
• Power greatly influenced by D, selection
  strategy,
• allele frequency
• Optimal linkage strategies not necessarily best
  for
• association
• Allele frequency of (unobserved) QTL is
  important,
• but more important that marker-QTL match