1 / 25

Power to detect QTL Association

Power to detect QTL Association . Lon Cardon, Goncalo Abecasis University of Oxford Pak Sham, Shaun Purcell Institute of Psychiatry. F:lon2001Assocpower. Association Power. In principle, power to detect association involves same mechanics as linkage . We are interested in

dunn
Download Presentation

Power to detect QTL Association

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. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Power to detect QTL Association Lon Cardon, Goncalo Abecasis University of Oxford Pak Sham, Shaun Purcell Institute of Psychiatry F:\lon\2001\Assocpower

  2. 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

  3. 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

  4. 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

  5. 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

  6. Extent of Disequilibrium

  7. Pair-wise Disequilibrium

  8. Sensitivity to Disequilibrium Power for =0.001, h² = .1, s² = .3,  = 0. Average additive genetic value estimated at the marker.

  9. 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

  10. Effect of Family Structure 350 sib-pair + parents: 1400 genotypes 500 sib-pairs – no parents: 1000 genotypes 260 sib-trios no parents: 780 genotypes

  11. 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 > 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

  12. Extent of Disequilibrium

  13. 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

  14. Trios For Genome-Wide Scan ls = 1.5, a = 5 x 10-8, Spielman TDT (Müller-Myhsok and Abel, 1997)

  15. Effect of Allele Frequencies

  16. 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

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

  18. 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

  19. Intensity of a priori selection

  20. Selection of Triads

  21. Post hoc Selection

  22. Effect of Allele Frequencies

  23. Effect of Selection

  24. 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

More Related