title: Whole genome association mapping by incompatibilities and local perfect phylogenies.
abstract: BACKGROUND
  With current technology, vast amounts of data can be cheaply and efficiently produced in association studies, and to prevent data analysis to become the bottleneck of studies, fast and efficient analysis methods that scale to such data set sizes must be developed.
  
  
  RESULTS
  We present a fast method for accurate localisation of disease causing variants in high density case-control association mapping experiments with large numbers of cases and controls. The method searches for significant clustering of case chromosomes in the "perfect" phylogenetic tree defined by the largest region around each marker that is compatible with a single phylogenetic tree. This perfect phylogenetic tree is treated as a decision tree for determining disease status, and scored by its accuracy as a decision tree. The rationale for this is that the perfect phylogeny near a disease affecting mutation should provide more information about the affected/unaffected classification than random trees. If regions of compatibility contain few markers, due to e.g. large marker spacing, the algorithm can allow the inclusion of incompatibility markers in order to enlarge the regions prior to estimating their phylogeny. Haplotype data and phased genotype data can be analysed. The power and efficiency of the method is investigated on 1) simulated genotype data under different models of disease determination 2) artificial data sets created from the HapMap ressource, and 3) data sets used for testing of other methods in order to compare with these. Our method has the same accuracy as single marker association (SMA) in the simplest case of a single disease causing mutation and a constant recombination rate. However, when it comes to more complex scenarios of mutation heterogeneity and more complex haplotype structure such as found in the HapMap data our method outperforms SMA as well as other fast, data mining approaches such as HapMiner and Haplotype Pattern Mining (HPM) despite being significantly faster. For unphased genotype data, an initial step of estimating the phase only slightly decreases the power of the method. The method was also found to accurately localise the known susceptibility variants in an empirical data set--the DeltaF508 mutation for cystic fibrosis--where the susceptibility variant is already known--and to find significant signals for association between the CYP2D6 gene and poor drug metabolism, although for this dataset the highest association score is about 60 kb from the CYP2D6 gene.
  
  
  CONCLUSIONS
  Our method has been implemented in the Blossoc (BLOck aSSOCiation) software. Using Blossoc, genome wide chip-based surveys of 3 million SNPs in 1000 cases and 1000 controls can be analysed in less than two CPU hours.
authors.affiliation: Department of Statistics, University of Oxford, UK. mailund@stats.ox.ac.uk
authors.forename: Thomas
authors.initials: T
authors.lastname: Mailund
authors.forename: Søren
authors.initials: S
authors.lastname: Besenbacher
authors.forename: Mikkel H
authors.initials: MH
authors.lastname: Schierup
mesh_terms: D002874:Chromosome Mapping / Q000379:methods*; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D019389:Cytochrome P-450 CYP2D6