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SNP-SNP interactions discovered by logic regression explain Crohn's disease genetics.

ABSTRACT: In genome-wide association studies (GWAS), the association between each single nucleotide polymorphism (SNP) and a phenotype is assessed statistically. To further explore genetic associations in GWAS, we considered two specific forms of biologically plausible SNP-SNP interactions, 'SNP intersection' and 'SNP union,' and analyzed the Crohn's Disease (CD) GWAS data of the Wellcome Trust Case Control Consortium for these interactions using a limited form of logic regression. We found strong evidence of CD-association for 195 genes, identifying novel susceptibility genes (e.g., ISX, SLCO6A1, TMEM183A) as well as confirming many previously identified susceptibility genes in CD GWAS (e.g., IL23R, NOD2, CYLD, NKX2-3, IL12RB2, ATG16L1). Notably, 37 of the 59 chromosomal locations indicated for CD-association by a meta-analysis of CD GWAS, involving over 22,000 cases and 29,000 controls, were represented in the 195 genes, as well as some chromosomal locations previously indicated only in linkage studies, but not in GWAS. We repeated the analysis with two smaller GWASs from the Database of Genotype and Phenotype (dbGaP): in spite of differences of populations and study power across the three datasets, we observed some consistencies across the three datasets. Notable examples included TMEM183A and SLCO6A1 which exhibited strong evidence consistently in our WTCCC and both of the dbGaP SNP-SNP interaction analyses. Examining these specific forms of SNP interactions could identify additional genetic associations from GWAS. R codes, data examples, and a ReadMe file are available for download from our website: http://www.ualberta.ca/~yyasui/homepage.html.

SUBMITTER: Dinu I

PROVIDER: S-EPMC3470545 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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SNP-SNP interactions discovered by logic regression explain Crohn's disease genetics.

Dinu Irina I Mahasirimongkol Surakameth S Liu Qi Q Yanai Hideki H Sharaf Eldin Noha N Kreiter Erin E Wu Xuan X Jabbari Shahab S Tokunaga Katsushi K Yasui Yutaka Y

PloS one 20121012 10

In genome-wide association studies (GWAS), the association between each single nucleotide polymorphism (SNP) and a phenotype is assessed statistically. To further explore genetic associations in GWAS, we considered two specific forms of biologically plausible SNP-SNP interactions, 'SNP intersection' and 'SNP union,' and analyzed the Crohn's Disease (CD) GWAS data of the Wellcome Trust Case Control Consortium for these interactions using a limited form of logic regression. We found strong evidenc ...[more]

PMID: 23071489

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Project description:In countries with a high incidence of tuberculosis, the typical clinical features of Crohn's disease (CD) may be covered up after tuberculosis infection, and the identification of atypical Crohn's disease and intestinal tuberculosis (ITB) is still a dilemma for clinicians. Least absolute shrinkage and selection operator (LASSO) regression has been applied to select variables in disease diagnosis. However, its value in discriminating ITB and atypical Crohn's disease remains unknown. A total of 400 patients were enrolled from January 2014 to January 2019 in second Xiangya hospital Central South University.Among them, 57 indicators including clinical manifestations, laboratory results, endoscopic findings, computed tomography enterography features were collected for further analysis. R software version 3.6.1 (glmnet package) was used to perform the LASSO logistic regression analysis. SPSS 20.0 was used to perform Pearson chi-square test and binary logistic regression analysis. In the variable selection step, LASSO regression and Pearson chi-square test were applied to select the most valuable variables as candidates for further logistic regression analysis. Secondly, variables identified from step 1 were applied to construct binary logistic regression analysis. Receiver operating characteristic (ROC) curve analysis was performed on these models to assess the ability and the optimal cutoff value for diagnosis. The area under the ROC curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy rate, together with their 95% confidence and intervals (CIs) were calculated. MedCalc software (Version 16.8) was applied to analyze the ROC curves of models. 332 patients were eventually enrolled to build a binary logistic regression model to discriminate CD (including comprehensive CD and tuberculosis infected CD) and ITB. However, we did not get a satisfactory diagnostic value via applying the binary logistic regression model of comprehensive CD and ITB to predict tuberculosis infected CD and ITB (accuracy rate:79.2%VS 65.1%). Therefore, we further established a binary logistic regression model to discriminate atypical CD from ITB, based on Pearsonchi-square test (model1) and LASSO regression (model 2). Model 1 showed 89.9% specificity, 65.9% sensitivity, 88.5% PPV, 68.9% NPV, 76.9% diagnostic accuracy, and an AUC value of 0.811, and model 2 showed 80.6% specificity, 84.4% sensitivity, 82.3% PPV, 82.9% NPV, 82.6% diagnostic accuracy, and an AUC value of 0.887. The comparison of AUCs between model1 and model2 was statistically different (P < 0.05). Tuberculosis infection increases the difficulty of discriminating CD from ITB. LASSO regression showed a more efficient ability than Pearson chi-square test based logistic regression on differential diagnosing atypical CD and ITB.

Dataset Information

SNP-SNP interactions discovered by logic regression explain Crohn's disease genetics.

Publications

SNP-SNP interactions discovered by logic regression explain Crohn's disease genetics.

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