Robust Reference Powered Association Test of Genome-Wide Association Studies.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC6465778 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Project description:MotivationGenome-wide association studies (GWASs) have been widely used to map loci contributing to variation in complex traits and risk of diseases in humans. Accurate specification of familial relationships is crucial for family-based GWAS, as well as in population-based GWAS with unknown (or unrecognized) family structure. The family structure in a GWAS should be routinely investigated using the SNP data prior to the analysis of population structure or phenotype. Existing algorithms for relationship inference have a major weakness of estimating allele frequencies at each SNP from the entire sample, under a strong assumption of homogeneous population structure. This assumption is often untenable.ResultsHere, we present a rapid algorithm for relationship inference using high-throughput genotype data typical of GWAS that allows the presence of unknown population substructure. The relationship of any pair of individuals can be precisely inferred by robust estimation of their kinship coefficient, independent of sample composition or population structure (sample invariance). We present simulation experiments to demonstrate that the algorithm has sufficient power to provide reliable inference on millions of unrelated pairs and thousands of relative pairs (up to 3rd-degree relationships). Application of our robust algorithm to HapMap and GWAS datasets demonstrates that it performs properly even under extreme population stratification, while algorithms assuming a homogeneous population give systematically biased results. Our extremely efficient implementation performs relationship inference on millions of pairs of individuals in a matter of minutes, dozens of times faster than the most efficient existing algorithm known to us.AvailabilityOur robust relationship inference algorithm is implemented in a freely available software package, KING, available for download at http://people.virginia.edu/?wc9c/KING.
| S-EPMC3025716 | biostudies-literature
Project description:In genetic association studies, due to the varying underlying genetic models, no single statistical test can be the most powerful test under all situations. Current studies show that if the underlying genetic models are known, trend-based tests, which outperform the classical Pearson χ² test, can be constructed. However, when the underlying genetic models are unknown, the χ² test is usually more robust than trend-based tests. In this paper, we propose a new association test based on a generalized genetic model, namely the generalized order-restricted relative risks model. Through a Monte Carlo simulation study, we show that the proposed association test is generally more powerful than the χ² test, and more robust than those trend-based tests. The proposed methodologies are also illustrated by some real SNP datasets.
| S-EPMC3322627 | biostudies-literature
Project description:In genome-wide association study (GWAS), robust genetic association tests such as maximum of three CATTs (MAX3), each corresponding to recessive, additive, and dominant genetic models, the minimum p value of Pearson's Chi-square test with 2 degrees of freedom, and CATT based on additive genetic model (MIN2), genetic model selection (GMS), and genetic model exclusion (GME) methods have been shown to provide better power performance under wide range of underlying genetic models. In this paper, we demonstrate how these robust tests can be applied to the replication study of GWAS and how the overall statistical significance can be evaluated using the combined test formed by p values of the discovery and replication studies.
| S-EPMC4539975 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have successfully discovered hundreds of associations between genetic variants and complex traits. Most GWAS have focused on the identification of single variants. It has been shown that most of the variants that were discovered by GWAS could only partially explain disease heritability. The explanation for this missing heritability is generally believed to be gene-gene (GG) or gene-environment (GE) interactions and other structural variants. Generalized multifactor dimensionality reduction (GMDR) has been proven to be reasonably powerful in detecting GG and GE interactions; however, its performance has been found to decline when outlying quantitative traits are present. This paper proposes a robust GMDR estimation method (based on the L-estimator and M-estimator estimation methods) in an attempt to reduce the effects caused by outlying traits. A comparison of robust GMDR with the original MDR based on simulation studies showed the former method to outperform the latter. The performance of robust GMDR is illustrated through a real GWA example consisting of 8,577 samples from the Korean population using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) level as a phenotype. Robust GMDR identified the KCNH1 gene to have strong interaction effects with other genes on the function of insulin secretion.
| S-EPMC4534386 | biostudies-literature
Project description:BackgroundGenome-wide association studies can provide novel insights into diseases of interest, as well as to the responsiveness of an individual to specific treatments. In such studies, it is very important to correct for population stratification, which refers to allele frequency differences between cases and controls due to systematic ancestry differences. Population stratification can cause spurious associations if not adjusted properly. The principal component analysis (PCA) method has been relied upon as a highly useful methodology to adjust for population stratification in these types of large-scale studies. Recently, the linear mixed model (LMM) has also been proposed to account for family structure or cryptic relatedness. However, neither of these approaches may be optimal in properly correcting for sample structures in the presence of subject outliers.ResultsWe propose to use robust PCA combined with k-medoids clustering to deal with population stratification. This approach can adjust for population stratification for both continuous and discrete populations with subject outliers, and it can be considered as an extension of the PCA method and the multidimensional scaling (MDS) method. Through simulation studies, we compare the performance of our proposed methods with several widely used stratification methods, including PCA and MDS. We show that subject outliers can greatly influence the analysis results from several existing methods, while our proposed robust population stratification methods perform very well for both discrete and admixed populations with subject outliers. We illustrate the new method using data from a rheumatoid arthritis study.ConclusionsWe demonstrate that subject outliers can greatly influence the analysis result in GWA studies, and propose robust methods for dealing with population stratification that outperform existing population stratification methods in the presence of subject outliers.
| S-EPMC3637636 | biostudies-literature
Project description:Genome-wide association studies are widely used today to discover genetic factors that modify the risk of complex diseases. Usually, these methods work in a SNP-by-SNP fashion. We present a gene-based test that can be applied in the context of genome-wide association studies. We compare both strategies, SNP-based and gene-based, in a sample of cases and controls for rheumatoid arthritis.We obtained different results using each strategy. The SNP-based test found the PTPN22 gene while the gene-based test found the PHF19-TRAF1-C5 region. That suggests that no single strategy performs better than another in all cases and that a certain underlying genetic architecture can be delineated more easily with one strategy rather than with another.
| S-EPMC2795904 | biostudies-literature
Project description:We have derived a versatile gene-based test for genome-wide association studies (GWAS). Our approach, called VEGAS (versatile gene-based association study), is applicable to all GWAS designs, including family-based GWAS, meta-analyses of GWAS on the basis of summary data, and DNA-pooling-based GWAS, where existing approaches based on permutation are not possible, as well as singleton data, where they are. The test incorporates information from a full set of markers (or a defined subset) within a gene and accounts for linkage disequilibrium between markers by using simulations from the multivariate normal distribution. We show that for an association study using singletons, our approach produces results equivalent to those obtained via permutation in a fraction of the computation time. We demonstrate proof-of-principle by using the gene-based test to replicate several genes known to be associated on the basis of results from a family-based GWAS for height in 11,536 individuals and a DNA-pooling-based GWAS for melanoma in approximately 1300 cases and controls. Our method has the potential to identify novel associated genes; provide a basis for selecting SNPs for replication; and be directly used in network (pathway) approaches that require per-gene association test statistics. We have implemented the approach in both an easy-to-use web interface, which only requires the uploading of markers with their association p-values, and a separate downloadable application.
| S-EPMC2896770 | biostudies-literature
Project description:BACKGROUND:Current robust association tests for case-control genome-wide association study (GWAS) data are mainly based on the assumption of some specific genetic models. Due to the richness of the genetic models, this assumption may not be appropriate. Therefore, robust but powerful association approaches are desirable. RESULTS:In this paper, we propose a new approach to testing for the association between the genotype and phenotype for case-control GWAS. This method assumes a generalized genetic model and is based on the selected disease allele to obtain a p-value from the more powerful one-sided test. Through a comprehensive simulation study we assess the performance of the new test by comparing it with existing methods. Some real data applications are also used to illustrate the use of the proposed test. CONCLUSIONS:Based on the simulation results and real data application, the proposed test is powerful and robust.
| S-EPMC4059871 | biostudies-other
Project description:Recent progress in the development of single-nucleotide polymorphism (SNP) maps within genes and across the genome provides a valuable tool for fine-mapping and has led to the suggestion of genomewide association studies to search for susceptibility loci for complex traits. Test statistics for genome association studies that consider a single marker at a time, ignoring the linkage disequilibrium between markers, are inefficient. In this study, we present a generalized T2 statistic for association studies of complex traits, which can utilize multiple SNP markers simultaneously and considers the effects of multiple disease-susceptibility loci. This generalized T2 statistic is a corollary to that originally developed for multivariate analysis and has a close relationship to discriminant analysis and common measure of genetic distance. We evaluate the power of the generalized T2 statistic and show that power to be greater than or equal to those of the traditional chi2 test of association and a similar haplotype-test statistic. Finally, examples are given to evaluate the performance of the proposed T2 statistic for association studies using simulated and real data.
| S-EPMC447600 | biostudies-other
Project description:SummaryHigh-throughput genotyping arrays provide an efficient way to survey single nucleotide polymorphisms (SNPs) across the genome in large numbers of individuals. Downstream analysis of the data, for example in genome-wide association studies (GWAS), often involves statistical models of genotype frequencies across individuals. The complexities of the sample collection process and the potential for errors in the experimental assay can lead to biases and artefacts in an individual's inferred genotypes. Rather than attempting to model these complications, it has become a standard practice to remove individuals whose genome-wide data differ from the sample at large. Here we describe a simple, but robust, statistical algorithm to identify samples with atypical summaries of genome-wide variation. Its use as a semi-automated quality control tool is demonstrated using several summary statistics, selected to identify different potential problems, and it is applied to two different genotyping platforms and sample collections.AvailabilityThe algorithm is written in R and is freely available at www.well.ox.ac.uk/chris-spencerContactchris.spencer@well.ox.ac.ukSupplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC3244763 | biostudies-literature