title: EPIQ-efficient detection of SNP-SNP epistatic interactions for quantitative traits.
abstract: BACKGROUND
  Gene-gene interactions are of potential biological and medical interest, as they can shed light on both the inheritance mechanism of a trait and on the underlying biological mechanisms. Evidence of epistatic interactions has been reported in both humans and other organisms. Unlike single-locus genome-wide association studies (GWAS), which proved efficient in detecting numerous genetic loci related with various traits, interaction-based GWAS have so far produced very few reproducible discoveries. Such studies introduce a great computational and statistical burden by necessitating a large number of hypotheses to be tested including all pairs of single nucleotide polymorphisms (SNPs). Thus, many software tools have been developed for interaction-based case-control studies, some leading to reliable discoveries. For quantitative data, on the other hand, only a handful of tools exist, and the computational burden is still substantial.
  
  
  RESULTS
  We present an efficient algorithm for detecting epistasis in quantitative GWAS, achieving a substantial runtime speedup by avoiding the need to exhaustively test all SNP pairs using metric embedding and random projections. Unlike previous metric embedding methods for case-control studies, we introduce a new embedding, where each SNP is mapped to two Euclidean spaces. We implemented our method in a tool named EPIQ (EPIstasis detection for Quantitative GWAS), and we show by simulations that EPIQ requires hours of processing time where other methods require days and sometimes weeks. Applying our method to a dataset from the Ludwigshafen risk and cardiovascular health study, we discovered a pair of SNPs with a near-significant interaction (P = 2.2 × 10(-13)), in only 1.5 h on 10 processors.
  
  
  BACKGROUND
  https://github.com/yaarasegre/EPIQ
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-8036, Austria, Synlab Academy, Synlab Services GmbH, Mannheim D-68165, Germany, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel and International Computer Science Institute, Berkeley, CA 94704, USA.
authors.forename: Ya'ara
authors.initials: Y
authors.lastname: Arkin
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-8036, Austria, Synlab Academy, Synlab Services GmbH, Mannheim D-68165, Germany, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel and International Computer Science Institute, Berkeley, CA 94704, USA.
authors.forename: Elior
authors.initials: E
authors.lastname: Rahmani
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-8036, Austria, Synlab Academy, Synlab Services GmbH, Mannheim D-68165, Germany, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel and International Computer Science Institute, Berkeley, CA 94704, USA.
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-8036, Austria, Synlab Academy, Synlab Services GmbH, Mannheim D-68165, Germany, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel and International Computer Science Institute, Berkeley, CA 94704, USAThe Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-8036, Austria, Synlab Academy, Synlab Services GmbH, Mannheim D-68165, Germany, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel and International Computer Science Institute, Berkeley, CA 94704, USA.
authors.forename: Reijo
authors.initials: R
authors.lastname: Laaksonen
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-8036, Austria, Synlab Academy, Synlab Services GmbH, Mannheim D-68165, Germany, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel and International Computer Science Institute, Berkeley, CA 94704, USAThe Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-8036, Austria, Synlab Academy, Synlab Services GmbH, Mannheim D-68165, Germany, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel and International Computer Science Institute, Berkeley, CA 94704, USAThe Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-803
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-8036, Austria, Synlab Academy, Synlab Services GmbH, Mannheim D-68165, Germany, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel and International Computer Science Institute, Berkeley, CA 94704, USAThe Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-8036, Austria, Synlab Academy, Synlab Services GmbH, Mannheim D-68165, Germany, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel and International Computer Science Institute, Berkeley, CA 94704, USAThe Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel, V Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim D-68167, Germany, Zora Biosciences Oy, Espoo 02150, Finland, Medical School, University of Tampere, Tampere 33104, Finland, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz A-803
authors.forename: Eran
authors.initials: E
authors.lastname: Halperin
mesh_terms: D000465:Algorithms; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012984:Software