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.

... 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

.... One example is {(SNP1, SNP5), (SNP1, SNP7), (SNP1, SNP9)}. Consequently, the detection of these 17 SNP pairs indicates that there is a four-locus interaction between MUC21 (mucin 21, cell surface associated), MUC22 (mucin 22), PSORS1C1 (psoriasis susceptibility 1 candidate 1) and TCF19 (transcription factor 19). In contrast, there are no interactions between ATAD1 (ATPase family, AAA domain containing 1) and the other genes due to the absence of a SNP pair containing a SNP from ATAD1 and a SNP

... 2 rs2523929 3 rs2530699 MUC22 6p21.33 4 rs9262546 5 rs6933349 6 rs4713423 PSORS1C1 6p21.3 7 rs9263715 8 rs9263716 TCF19 6p21.3 9 rs9263794 ATAD1 10q23.31 10 rs12775041 11 rs12573160 12 rs12781171 Twenty SNP pairs are present in the ensemble. A pair of dots in the same column denotes a SNP pair. Figure 3 LD patterns of SNPs within or near MUC21 , MUC22 , PSORS1C1 , TCF19 and ATAD1 . LD is explained by D displayed in the upper triangle and r 2 displayed in the lower triangle. Dark colours indicate high values while pale colours indicate low values. Distances between SNPs are given in terms of the number of base pairs. SNP1 = rs2844678, SNP2 = rs2523929, SNP3 = rs2530699, SNP4 = rs9262546, SNP5 = rs6933349, SNP6 = rs4713423, SNP7 = rs9263715, SNP8 = rs9263716, SNP9 = rs9263794, SNP10 = rs12775041, SNP11 = rs12573160 and SNP12 = rs12781171. The first four genes identified by 2LOmb, namely MUC21 , MUC22 , PSORS1C1 and TCF19 , are located on the major histocompatibility complex (MHC). MHC is a genomic region in which a mouse model of human complex diseases suggests the presence of T1D susceptibility genes (Cordell et al. 2001 ). The four genes are also located between DDR1 (discoidin domain receptor tyrosine kinase 1) and HLA-DQA1 (major histocompatibility complex

... among many candidate genes for the association studies of Parkinsons disease. Nonetheless, there is little information about pathways that include ATAD1 (Moran and Graeber 2008 ). Hence, it is impossible to explain the association between ATAD1 polymorphisms and T1D at this point. This study produces evidence of association between 12 SNPs within or near MUC21 , MUC22 , PSORS1C1 , TCF19 and ATAD1 , and T1D in a UK population. Although there are other independent genome-wide T1D data sets, the

... data set is further reduced by removing SNPs that exhibit marginal single-locus effects or have MAFs below 0.1. The final data set contains 95,991 SNPs from 12,146 genes. 2LOmb identifies 12 SNPs that are associated with the disease. These SNPs are located within or near MUC21 , MUC22 , PSORS1C1 , TCF19 and ATAD1 . 2LOmb and LD analyses indicate that there is a four-locus interaction between MUC21 , MUC22 , PSORS1C1 and TCF19 while SNPs from ATAD1 are independently associated with the disease. This

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Gene: MUC22 - mucin 22 - (NCBI)

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