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Stability of bivariate GWAS biomarker detection.

ABSTRACT: Given the difficulty and effort required to confirm candidate causal SNPs detected in genome-wide association studies (GWAS), there is no practical way to definitively filter false positives. Recent advances in algorithmics and statistics have enabled repeated exhaustive search for bivariate features in a practical amount of time using standard computational resources, allowing us to use cross-validation to evaluate the stability. We performed 10 trials of 2-fold cross-validation of exhaustive bivariate analysis on seven Wellcome-Trust Case-Control Consortium GWAS datasets, comparing the traditional [Formula: see text] test for association, the high-performance GBOOST method and the recently proposed GSS statistic (Available at http://bioinformatics.research.nicta.com.au/software/gwis/). We use Spearman's correlation to measure the similarity between the folds of cross validation. To compare incomplete lists of ranks we propose an extension to Spearman's correlation. The extension allows us to consider a natural threshold for feature selection where the correlation is zero. This is the first reported cross-validation study of exhaustive bivariate GWAS feature selection. We found that stability between ranked lists from different cross-validation folds was higher for GSS in the majority of diseases. A thorough analysis of the correlation between SNP-frequency and univariate [Formula: see text] score demonstrated that the [Formula: see text] test for association is highly confounded by main effects: SNPs with high univariate significance replicably dominate the ranked results. We show that removal of the univariately significant SNPs improves [Formula: see text] replicability but risks filtering pairs involving SNPs with univariate effects. We empirically confirm that the stability of GSS and GBOOST were not affected by removal of univariately significant SNPs. These results suggest that the GSS and GBOOST tests are successfully targeting bivariate association with phenotype and that GSS is able to reliably detect a larger set of SNP-pairs than GBOOST in the majority of the data we analysed. However, the [Formula: see text] test for association was confounded by main effects.

SUBMITTER: Bedo J

PROVIDER: S-EPMC4005767 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Stability of bivariate GWAS biomarker detection.

Bedő Justin J Rawlinson David D Goudey Benjamin B Ong Cheng Soon CS

PloS one 20140430 4

Given the difficulty and effort required to confirm candidate causal SNPs detected in genome-wide association studies (GWAS), there is no practical way to definitively filter false positives. Recent advances in algorithmics and statistics have enabled repeated exhaustive search for bivariate features in a practical amount of time using standard computational resources, allowing us to use cross-validation to evaluate the stability. We performed 10 trials of 2-fold cross-validation of exhaustive b ...[more]

PMID: 24787002

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Project description:Recently, new loci related to body mass index (BMI) or blood pressure (BP) have been identified respectively in genome-wide association studies (GWAS). However, limited studies focused on jointly associated genetic variance between systolic pressure (SBP), diastolic pressure (DBP) and BMI. Therefore, a bivariate twin study was performed to explore the genetic variants associated with BMI-SBP, BMI-DBP and SBP-DBP. A total of 380 twin pairs (137 dizygotic pairs and 243 monozygotic pairs) recruited from Qingdao Twin Registry system were used to access the genetic correlations (0.2108 for BMI-SBP, 0.2345 for BMI-DBP, and 0.6942 for SBP-DBP, respectively) by bivariate Cholesky decomposition model. Bivariate GWAS in 137 dizygotic pairs nominated 27 single identified 27 quantitative trait nucleotides (QTNs) for BMI and SBP, 27 QTNs for BMI and DBP, and 25 QTNs for SBP and DBP with the suggestive P-value threshold of 1×10-5. After imputation, we found eight SNPs, one for both BMI-SBP and SBP-DBP, and eight for SBP-DBP, exceed significant statistic level. Expression quantitative trait loci analysis identified rs4794029 as new significant eQTL in tissues related to BMI and SBP. Also, we found 6 new significant eQTLs (rs4400367, rs10113750, rs11776003, rs3739327, rs55978930, and rs4794029) in tissues were related to SBP and DBP. Gene-based analysis identified nominally associated genes (P < 0.05) with BMI-SBP, BMI-DBP, and SBP-DBP, respectively, such as PHOSPHO1, GNGT2, KEAP1, and S1PR5. In the pathway analysis, we found some pathways associated with BMI-SBP, BMI-DBP and SBP-DBP, such as prion diseases, IL5 pathway, cyclin E associated events during G1/S transition, TGF beta signaling pathway, G βγ signaling through PI3Kγ, prolactin receptor signaling etc. These findings may enrich the results of genetic variants related to BMI and BP traits, and provide some evidences to future study the pathogenesis of hypertension and obesity in the northern Chinese population.

Dataset Information

Stability of bivariate GWAS biomarker detection.

Publications

Stability of bivariate GWAS biomarker detection.

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