title: An omnibus permutation test on ensembles of two-locus analyses can detect pure epistasis and genetic heterogeneity in genome-wide association studies.
abstract: This article presents the ability of an omnibus permutation test on ensembles of two-locus analyses (2LOmb) to detect pure epistasis in the presence of genetic heterogeneity. The performance of 2LOmb is evaluated in various simulation scenarios covering two independent causes of complex disease where each cause is governed by a purely epistatic interaction. Different scenarios are set up by varying the number of available single nucleotide polymorphisms (SNPs) in data, number of causative SNPs and ratio of case samples from two affected groups. The simulation results indicate that 2LOmb outperforms multifactor dimensionality reduction (MDR) and random forest (RF) techniques in terms of a low number of output SNPs and a high number of correctly-identified causative SNPs. Moreover, 2LOmb is capable of identifying the number of independent interactions in tractable computational time and can be used in genome-wide association studies. 2LOmb is subsequently applied to a type 1 diabetes mellitus (T1D) data set, which is collected from a UK population by the Wellcome Trust Case Control Consortium (WTCCC). After screening for SNPs that locate within or near genes and exhibit no marginal single-locus effects, the T1D data set is reduced to 95,991 SNPs from 12,146 genes. The 2LOmb search in the reduced T1D data set reveals that 12 SNPs, which can be divided into two independent sets, are associated with the disease. The first SNP set consists of three SNPs from MUC21 (mucin 21, cell surface associated), three SNPs from MUC22 (mucin 22), two SNPs from PSORS1C1 (psoriasis susceptibility 1 candidate 1) and one SNP from TCF19 (transcription factor 19). A four-locus interaction between these four genes is also detected. The second SNP set consists of three SNPs from ATAD1 (ATPase family, AAA domain containing 1). Overall, the findings indicate the detection of pure epistasis in the presence of genetic heterogeneity and provide an alternative explanation for the aetiology of T1D in the UK population.
authors.affiliation: Department of Electrical and Computer Engineering, Faculty of Engineering, King Mongkut's University of Technology North Bangkok, 1518 Pracharat Sai 1 Road, Bangsue, Bangkok 10800, Thailand.
authors.forename: Damrongrit
authors.initials: D
authors.lastname: Setsirichok
authors.affiliation: Department of Electrical and Computer Engineering, Faculty of Engineering, King Mongkut's University of Technology North Bangkok, 1518 Pracharat Sai 1 Road, Bangsue, Bangkok 10800, Thailand.
authors.forename: Phuwadej
authors.initials: P
authors.lastname: Tienboon
authors.affiliation: Department of Computer Engineering, Faculty of Engineering, King Mongkut's University of Technology Thonburi, 126 Pracha-utid Road, Bangmod, Toongkru, Bangkok 10140, Thailand.
authors.forename: Nattapong
authors.initials: N
authors.lastname: Jaroonruang
authors.affiliation: Department of Electrical and Computer Engineering, Faculty of Engineering, King Mongkut's University of Technology North Bangkok, 1518 Pracharat Sai 1 Road, Bangsue, Bangkok 10800, Thailand.
authors.forename: Somkit
authors.initials: S
authors.lastname: Kittichaijaroen
authors.affiliation: Division of Technology of Information System Management, Faculty of Engineering, Mahidol University, 25/25 Phuttamonthon 4 Road, Nakhon Pathom 73170, Salaya, Thailand.
authors.forename: Waranyu
authors.initials: W
authors.lastname: Wongseree
authors.affiliation: Department of Electrical and Computer Engineering, Faculty of Engineering, King Mongkut's University of Technology North Bangkok, 1518 Pracharat Sai 1 Road, Bangsue, Bangkok 10800, Thailand.
authors.forename: Theera
authors.initials: T
authors.lastname: Piroonratana
authors.affiliation: Department of Electrical and Computer Engineering, Faculty of Engineering, King Mongkut's University of Technology North Bangkok, 1518 Pracharat Sai 1 Road, Bangsue, Bangkok 10800, Thailand.
authors.forename: Touchpong
authors.initials: T
authors.lastname: Usavanarong
authors.affiliation: Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkok 10700, Bangkoknoi, Thailand.
authors.forename: Chanin
authors.initials: C
authors.lastname: Limwongse
authors.affiliation: Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Pathumwan, Bangkok 10330, Thailand.
authors.forename: Chatchawit
authors.initials: C
authors.lastname: Aporntewan
authors.affiliation: Department of Computer Engineering, Faculty of Engineering, King Mongkut's University of Technology Thonburi, 126 Pracha-utid Road, Bangmod, Toongkru, Bangkok 10140, Thailand.
authors.forename: Marong
authors.initials: M
authors.lastname: Phadoongsidhi
authors.affiliation: Department of Electrical and Computer Engineering, Faculty of Engineering, King Mongkut's University of Technology North Bangkok, 1518 Pracharat Sai 1 Road, Bangsue, Bangkok 10800, Thailand ; Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkok 10700, Bangkoknoi, Thailand.
authors.forename: Nachol
authors.initials: N
authors.lastname: Chaiyaratana
keywords: Attribute selection; Complex disease; Epistasis; Genetic heterogeneity; Genome-wide association study; Pattern recognition; Permutation test; Single nucleotide polymorphism; Type 1 diabetes mellitus