title: ABACUS: an entropy-based cumulative bivariate statistic robust to rare variants and different direction of genotype effect.
abstract: BACKGROUND
  In the past years, both sequencing and microarray have been widely used to search for relations between genetic variations and predisposition to complex pathologies such as diabetes or neurological disorders. These studies, however, have been able to explain only a small fraction of disease heritability, possibly because complex pathologies cannot be referred to few dysfunctional genes, but are rather heterogeneous and multicausal, as a result of a combination of rare and common variants possibly impairing multiple regulatory pathways. Rare variants, though, are difficult to detect, especially when the effects of causal variants are in different directions, i.e. with protective and detrimental effects.
  
  
  RESULTS
  Here, we propose ABACUS, an Algorithm based on a BivAriate CUmulative Statistic to identify single nucleotide polymorphisms (SNPs) significantly associated with a disease within predefined sets of SNPs such as pathways or genomic regions. ABACUS is robust to the concurrent presence of SNPs with protective and detrimental effects and of common and rare variants; moreover, it is powerful even when few SNPs in the SNP-set are associated with the phenotype. We assessed ABACUS performance on simulated and real data and compared it with three state-of-the-art methods. When ABACUS was applied to type 1 and 2 diabetes data, besides observing a wide overlap with already known associations, we found a number of biologically sound pathways, which might shed light on diabetes mechanism and etiology.
  
  
  METHODS
  ABACUS is available at http://www.dei.unipd.it/∼dicamill/pagine/Software.html.
authors.affiliation: Department of Information Engineering, University of Padova, via Gradenigo 6B, 35131 Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Camillo
authors.forename: Francesco
authors.initials: F
authors.lastname: Sambo
authors.forename: Gianna
authors.initials: G
authors.lastname: Toffolo
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
mesh_terms: D000465:Algorithms; D003627:Data Interpretation, Statistical; D005787:Gene Frequency; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide