title: JBASE: Joint Bayesian Analysis of Subphenotypes and Epistasis.
abstract: BACKGROUND
  Rapid advances in genotyping and genome-wide association studies have enabled the discovery of many new genotype-phenotype associations at the resolution of individual markers. However, these associations explain only a small proportion of theoretically estimated heritability of most diseases. In this work, we propose an integrative mixture model called JBASE: joint Bayesian analysis of subphenotypes and epistasis. JBASE explores two major reasons of missing heritability: interactions between genetic variants, a phenomenon known as epistasis and phenotypic heterogeneity, addressed via subphenotyping.
  
  
  RESULTS
  Our extensive simulations in a wide range of scenarios repeatedly demonstrate that JBASE can identify true underlying subphenotypes, including their associated variants and their interactions, with high precision. In the presence of phenotypic heterogeneity, JBASE has higher Power and lower Type 1 Error than five state-of-the-art approaches. We applied our method to a sample of individuals from Mexico with Type 2 diabetes and discovered two novel epistatic modules, including two loci each, that define two subphenotypes characterized by differences in body mass index and waist-to-hip ratio. We successfully replicated these subphenotypes and epistatic modules in an independent dataset from Mexico genotyped with a different platform.
  
  
  METHODS
  JBASE is implemented in C++, supported on Linux and is available at http://www.cs.toronto.edu/∼goldenberg/JBASE/jbase.tar.gz. The genotype data underlying this study are available upon approval by the ethics review board of the Medical Centre Siglo XXI. Please contact Dr Miguel Cruz at mcruzl@yahoo.com for assistance with the application.
  
  
  BACKGROUND
  anna.goldenberg@utoronto.ca
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Computer Science, University of Toronto, M5S 2E4, Toronto, ON, Canada, Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, M5S 3E1, Toronto, ON, Canada.
authors.forename: Recep
authors.initials: R
authors.lastname: Colak
authors.affiliation: Department of Computer Science, University of Toronto, M5S 2E4, Toronto, ON, Canada, Department of Computer Engineering, Antalya International University, 07190, Antalya, Turkey.
authors.forename: TaeHyung
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Computer Engineering, Antalya International University, 07190, Antalya, Turkey.
authors.forename: Hilal
authors.initials: H
authors.lastname: Kazan
authors.affiliation: Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, M5S 3E1, Toronto, ON, Canada, Department of Molecular Genetics, University of Toronto, M5S 1A8, Toronto, ON, Canada.
authors.forename: Yoomi
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, IMSS, 06720, Mexico City, Mexico.
authors.forename: Miguel
authors.initials: M
authors.lastname: Cruz
authors.affiliation: Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, IMSS, 06720, Mexico City, Mexico.
authors.forename: Adan
authors.initials: A
authors.lastname: Valladares-Salgado
authors.affiliation: Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, IMSS, 06720, Mexico City, Mexico.
authors.forename: Jesus
authors.initials: J
authors.lastname: Peralta
authors.affiliation: Unidad de Investigación en Epidemiología Clínica, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Escobedo
authors.affiliation: Department of Anthropology, University of Toronto, L5L 1C6, Mississauga, ON, Canada.
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Parra
authors.affiliation: Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, M5S 3E1, Toronto, ON, Canada, Department of Molecular Genetics, University of Toronto, M5S 1A8, Toronto, ON, Canada, Genetics and Genome Biology, Hospital for Sick Children, M5G 0A4, Toronto, ON, Canada and Banting and Best Department of Medical Research, University of Toronto, M5G 1L6, Toronto, ON, Canada.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kim
authors.affiliation: Department of Computer Science, University of Toronto, M5S 2E4, Toronto, ON, Canada, Genetics and Genome Biology, Hospital for Sick Children, M5G 0A4, Toronto, ON, Canada and.
authors.forename: Anna
authors.initials: A
authors.lastname: Goldenberg
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D004843:Epistasis, Genetic; D055106:Genome-Wide Association Study; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D008800:Mexico; D010641:Phenotype; D049629:Waist-Hip Ratio