title: Identifying gene-gene interactions that are highly associated with Body Mass Index using Quantitative Multifactor Dimensionality Reduction (QMDR).
abstract: BACKGROUND
  Despite heritability estimates of 40-70 % for obesity, less than 2 % of its variation is explained by Body Mass Index (BMI) associated loci that have been identified so far. Epistasis, or gene-gene interactions are a plausible source to explain portions of the missing heritability of BMI.
  
  
  METHODS
  Using genotypic data from 18,686 individuals across five study cohorts - ARIC, CARDIA, FHS, CHS, MESA - we filtered SNPs (Single Nucleotide Polymorphisms) using two parallel approaches. SNPs were filtered either on the strength of their main effects of association with BMI, or on the number of knowledge sources supporting a specific SNP-SNP interaction in the context of BMI. Filtered SNPs were specifically analyzed for interactions that are highly associated with BMI using QMDR (Quantitative Multifactor Dimensionality Reduction). QMDR is a nonparametric, genetic model-free method that detects non-linear interactions associated with a quantitative trait.
  
  
  RESULTS
  We identified seven novel, epistatic models with a Bonferroni corrected p-value of association < 0.1. Prior experimental evidence helps explain the plausible biological interactions highlighted within our results and their relationship with obesity. We identified interactions between genes involved in mitochondrial dysfunction (POLG2), cholesterol metabolism (SOAT2), lipid metabolism (CYP11B2), cell adhesion (EZR), cell proliferation (MAP2K5), and insulin resistance (IGF1R). Moreover, we found an 8.8 % increase in the variance in BMI explained by these seven SNP-SNP interactions, beyond what is explained by the main effects of an index FTO SNP and the SNPs within these interactions. We also replicated one of these interactions and 58 proxy SNP-SNP models representing it in an independent dataset from the eMERGE study.
  
  
  CONCLUSIONS
  This study highlights a novel approach for discovering gene-gene interactions by combining methods such as QMDR with traditional statistics.
authors.affiliation: Computational Genetics Laboratory, Department of Genetics, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, 706 Rubin Building, HB7937, One Medical Center Dr, Lebanon, NH 03756 USA.
authors.forename: Rishika
authors.initials: R
authors.lastname: De
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, 512 Wartik Laboratory, The Pennsylvania State University, University Park, PA 16802 USA.
authors.forename: Shefali S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, 5 University Street, London, WC1E 6JF UK.
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, 512 Wartik Laboratory, The Pennsylvania State University, University Park, PA 16802 USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Holzinger
authors.affiliation: Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 2 Dulles Pvln, Philadelphia, PA 19104 USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, 512 Wartik Laboratory, The Pennsylvania State University, University Park, PA 16802 USA.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Hall
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065 USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: Group Health Research Institute, Metropolitan Park East, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101-1448 USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Carrell
authors.affiliation: The Joseph Stokes Jr. Research Institute, The Children's Hospital of Philadelphia, Office 1016 Abramson Building, Room 1216E, 3615 Civic Center Blvd, Philadelphia, PA 19104 USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195-5065 USA ; Division of Medical Genetics, Department of Medicine, University of Washington, Health Sciences Building, K-253B, Medical Genetics, Box 357720, Seattle, WA 98195-7720 USA.
authors.forename: Gail
authors.initials: G
authors.lastname: Jarvik
authors.affiliation: Group Health Research Institute, Metropolitan Park East, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101-1448 USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Larson
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Lurie 7-125, Chicago, IL 60611 USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pacheco
authors.affiliation: Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, 680 N Lake Shore Drive, Suite 1400, Chicago, IL 60611 USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Rasmussen-Torvik
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, 512 Wartik Laboratory, The Pennsylvania State University, University Park, PA 16802 USA ; Center for Human Genetics Research, Vanderbilt University School of Medicine, 519 Light Hall, Nashville, TN 37232 USA.
authors.forename: Carrie B
authors.initials: CB
authors.lastname: Moore
authors.affiliation: Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Room E03.511, P.O. Box 85500, 3508 GA Utrecht, The Netherlands ; Institute of Cardiovascular Science, University College London, London, UK ; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Institute for Biomedical Informatics, The Perelman School of Medicine, University of Pennsylvania, 1418 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021 USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, 512 Wartik Laboratory, The Pennsylvania State University, University Park, PA 16802 USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: The Joseph Stokes Jr. Research Institute, The Children's Hospital of Philadelphia, Office 1016 Abramson Building, Room 1216E, 3615 Civic Center Blvd, Philadelphia, PA 19104 USA ; University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: Institute for Quantitative Biomedical Sciences at Dartmouth, Hanover, NH USA ; Department of Epidemiology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, 7927 Rubin Building, Lebanon, NH 03756 USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Gilbert-Diamond
keywords: Epistasis; GWAS; Gene-gene interaction; Multifactor dimensionality reduction; Obesity