Interactions In Genome-wide Association Studies Research Articles

Eigen-Epistasis for detecting gene-gene interactions

BackgroundA large amount of research has been devoted to the detection and investigation of epistatic interactions in genome-wide association studies (GWASs). Most of the literature focuses on low-order interactions between single-nucleotide polymorphisms (SNPs) with significant main effects.ResultsIn this paper we propose an original approach for detecting epistasis at the gene level, without systematically filtering on significant genes. We first compute interaction variables for each gene pair by finding its Eigen-Epistasis component, defined as the linear combination of Gene SNPs having the highest correlation with the phenotype. The selection of significant effects is done using a penalized regression method based on Group Lasso controlling the False Discovery Rate.ConclusionThe method is tested against two recent alternative proposals from the literature using synthetic data, and shows good performances in different settings. We demonstrate the power of our approach by detecting new gene-gene interactions on three genome-wide association studies.

Accounting for Population Structure in Gene-by-Environment Interactions in Genome-Wide Association Studies Using Mixed Models.

Although genome-wide association studies (GWASs) have discovered numerous novel genetic variants associated with many complex traits and diseases, those genetic variants typically explain only a small fraction of phenotypic variance. Factors that account for phenotypic variance include environmental factors and gene-by-environment interactions (GEIs). Recently, several studies have conducted genome-wide gene-by-environment association analyses and demonstrated important roles of GEIs in complex traits. One of the main challenges in these association studies is to control effects of population structure that may cause spurious associations. Many studies have analyzed how population structure influences statistics of genetic variants and developed several statistical approaches to correct for population structure. However, the impact of population structure on GEI statistics in GWASs has not been extensively studied and nor have there been methods designed to correct for population structure on GEI statistics. In this paper, we show both analytically and empirically that population structure may cause spurious GEIs and use both simulation and two GWAS datasets to support our finding. We propose a statistical approach based on mixed models to account for population structure on GEI statistics. We find that our approach effectively controls population structure on statistics for GEIs as well as for genetic variants.

Searching Genome-Wide Multi-Locus Associations for Multiple Diseases Based on Bayesian Inference.

Taking the advantage of high-throughput single nucleotide polymorphism (SNP) genotyping technology, large genome-wide association studies (GWASs) have been considered to hold promise for unraveling complex relationships between genotypes and phenotypes. Current multi-locus-based methods are insufficient to detect interactions with diverse genetic effects on multifarious diseases. Also, statistic tests for high-order epistasis ( ≥ 2 SNPs) raise huge computational and analytical challenges because the computation increases exponentially as the growth of the cardinality of SNPs combinations. In this paper, we provide a simple, fast and powerful method, named DAM, using Bayesian inference to detect genome-wide multi-locus epistatic interactions in multiple diseases. Experimental results on simulated data demonstrate that our method is powerful and efficient. We also apply DAM on two GWAS datasets from WTCCC, i.e., Rheumatoid Arthritis and Type 1 Diabetes, and identify some novel findings. Therefore, we believe that our method is suitable and efficient for the full-scale analysis of multi-disease-related interactions in GWASs.

Genome-wide Association Interaction Studies with MB-MDR and maxT Multiple Testing Correction on FPGAs

In the past few years massive amounts of data have been generated for genetic analysis. Existing solutions to analyze this data concerning genome-wide gene interactions are either not powerful enough or can barely be managed with standard computers due to the tremendous amount of statistical tests to be performed. Also, common approaches using cluster or cloud technologies for parallel analysis are operating at the edge of what is currently possible.This work demonstrates how FPGAs are able to address this problem. We present a highly parallel, hardware oriented solution for genome-wide association interaction studies (GWAIS) with MB-MDR and the maxT multiple testing correction on an FPGA-based architecture. We achieve a more than 300-fold speedup over an AMD Opteron cluster with 160 cores on an FPGA-system equipped with 128 Xilinx Spartan6 LX150 low-cost FPGAs when analyzing a WTCCC-like dataset with 500,000 markers and 5,000 samples. Furthermore, we are able to keep pace with a 256-core Intel Xeon cluster running MB-MDR 4.2.2 with an approximative version of maxT, while we achieve a 190-fold speedup over the sequential execution of this version on one Xeon core.

Is it possible to detect G×E interactions in GWAS when causal exposure is unobserved?

Background: It is generally acknowledged that most complex diseases are affected in part by interactions between genes andgenes and/or between genes and environmental factors. Taking into account environmental exposures and their interactionswith genetic factors in genome-wide association studies (GWAS) can help to identify high-risk subgroups in the population andprovide a better understanding of the disease. For this reason, many methods have been developed to detect gene-environment (G×E) interactions. Despite this, few loci that interact with environmental exposures have been identified so far. Indeed, themodest effect of G×E interactions as well as confounding factors entail low statistical power to detect such interactions. Anotherpotential obstacle to detect G×E interaction is the fact that true exposure is seldom observed: Indeed, only proxy effects aremeasured in general. Furthermore, power studies used to evaluate a new method often are done through simulations that give anadvantage to the new approach over the other methods.Methods: In this work, we compare the relative performance of popular methods such as PLINK, random forests and linearmixed models to detect G×E interactions in the particular scenario where the causal exposure (E) is unknown and only proxycovariates are observed. For this purpose, we provide an adapted simulated dataset and apply a recently introduced method for H1simulations called waffect.Results: When the causal environmental exposure is unobserved but only a proxy of this exposure is observed, all the methodsconsidered fail to detect G×E interaction.Conclusions: The hidden causal exposure is an obstacle to detect G×E interaction in GWAS and the approaches considered inour power study all have insufficient power to detect the strong simulated interaction.

A comment on two-locus epistatic interaction models for genome-wide association studies.

Detection of epistatic interactions in genome-wide association studies is a computationally hard problem. Many detection algorithms have been proposed and will continue to be. Most of those algorithms measure their predictive power by running on simulated data many times under various disease models. However, we find that there have been subtle differences in interpreting the meaning of existing disease models among the previous studies on detection of epistatic interactions. We elucidate those differences and suggest that future studies on epistatic interactions in GWAS state explicitly which versions/interpretations are employed. We also provide a way to facilitate setting parameters of disease models.

An Ant Colony Optimization and Tabu List Approach to the Detection of Gene-Gene Interactions in Genome-Wide Association Studies [Research Frontier

In this paper, a novel ant colony optimization and tabu list approach for the discovery of gene-gene interactions in genome-wide association study data is proposed. The method is tested on a number of diseases drawn from the large established database, the Wellcome Trust Case Control Consortium which contains hundreds of thousands of small DNA changes known as single nucleotide polymorphisms. To analyze full scale genome-wide association study data, the standard ant colony optimization algorithm has been adapted, with tournament path selection, a subset based approach, and tabu list included in the algorithm. These modifications, in addition to the use of a statistical test of significance of single nucleotide polymorphism interactions as a fitness function, greatly increase execution speeds and permit the discovery of combinations of single nucleotide polymorphisms that can discriminate cases and controls. The methodology is applied to several large-scale genome-wide association study disease datasets namely, inflammatory bowel disease, rheumatoid arthritis, type I diabetes and type II diabetes patients to discover putative gene-gene interactions in reasonable time on modest hardware.

Jackknife-based gene-gene interactiontests for untyped SNPs.

BackgroundTesting gene-gene interaction in genome-wide association studies generally yields lower power than testing marginal association. Meta-analysis that combines different genotyping platforms is one method used to increase power when assessing gene-gene interactions, which requires a test for interaction on untyped SNPs. However, to date, formal statistical tests for gene-gene interaction on untyped SNPs have not been thoroughly addressed. The key concern for gene-gene interaction testing on untyped SNPs located on different chromosomes is that the pair of genes might not be independent and the current generation of imputation methods provides imputed genotypes at the marginal accuracy.ResultsIn this study we address this challenge and describe a novel method for testing gene-gene interaction on marginally imputed values of untyped SNPs. We show that our novel Wald-type test statistics for interactions with and without constraints in the interaction parameters follow the asymptotic distributions which are the same as those of the corresponding tests for typed SNPs. Through simulations, we show that the proposed tests properly control type I error and are more powerful than the extension of the classical dosage method to interaction tests. The increase in power results from a proper correction for the uncertainty in imputation through the variance estimator using the jackknife, one of resampling techniques. We apply the method to detect interactions between SNPs on chromosomes 5 and 15 on lung cancer data. The inclusion of the results at the untyped SNPs provides a much more detailed information at the regions of interest.ConclusionsAs demonstrated by the simulation studies and real data analysis, our approaches outperform the application of traditional dosage method to detection of gene-gene interaction in terms of power while providing control of the type I error.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0225-9) contains supplementary material, which is available to authorized users.

High-speed exhaustive 3-locus interaction epistasis analysis on FPGAs

Epistasis, the interaction between genes, has become a major topic in molecular and quantitative genetics. It is believed that these interactions play a significant role in genetic variations causing complex diseases. Several algorithms have been employed to detect pairwise interactions in genome-wide association studies (GWAS) but revealing higher order interactions remains a computationally challenging task. State of the art tools are not able to perform exhaustive search for all three-locus interactions in reasonable time even for relatively small input datasets. In this paper we present how a hardware-assisted design can solve this problem and provide fast, efficient and exhaustive third-order epistasis analysis with up-to-date FPGA technology.

A FAST ALGORITHM FOR DETECTING GENE-GENE INTERACTIONS IN GENOME-WIDE ASSOCIATION STUDIES.

With the recent advent of high-throughput genotyping techniques, genetic data for genome-wide association studies (GWAS) have become increasingly available, which entails the development of efficient and effective statistical approaches. Although many such approaches have been developed and used to identify single-nucleotide polymorphisms (SNPs) that are associated with complex traits or diseases, few are able to detect gene-gene interactions among different SNPs. Genetic interactions, also known as epistasis, have been recognized to play a pivotal role in contributing to the genetic variation of phenotypic traits. However, because of an extremely large number of SNP-SNP combinations in GWAS, the model dimensionality can quickly become so overwhelming that no prevailing variable selection methods are capable of handling this problem. In this paper, we present a statistical framework for characterizing main genetic effects and epistatic interactions in a GWAS study. Specifically, we first propose a two-stage sure independence screening (TS-SIS) procedure and generate a pool of candidate SNPs and interactions, which serve as predictors to explain and predict the phenotypes of a complex trait. We also propose a rates adjusted thresholding estimation (RATE) approach to determine the size of the reduced model selected by an independence screening. Regularization regression methods, such as LASSO or SCAD, are then applied to further identify important genetic effects. Simulation studies show that the TS-SIS procedure is computationally efficient and has an outstanding finite sample performance in selecting potential SNPs as well as gene-gene interactions. We apply the proposed framework to analyze an ultrahigh-dimensional GWAS data set from the Framingham Heart Study, and select 23 active SNPs and 24 active epistatic interactions for the body mass index variation. It shows the capability of our procedure to resolve the complexity of genetic control.

An overview of SNP interactions in genome-wide association studies.

With the recent explosion in high-throughput genotyping technology, the amount and quality of single-nucleotide polymorphism (SNP) data has increased exponentially. Therefore, the identification of SNP interactions that are associated with common diseases is playing an increasing and important role in interpreting the genetic basis of disease susceptibility and in devising new diagnostic tests and treatments. However, because these data sets are large, although they typically have small sample sizes and low signal-to-noise ratios, there has been no major breakthrough despite many efforts, making this a major focus in the field of bioinformatics. In this article, we review the two main aspects of SNP interaction studies in recent years-the simulation and identification of SNP interactions-and then discuss the principles, efficiency and differences between these methods.

Cloud computing for detecting high-order genome-wide epistatic interaction via dynamic clustering

BackgroudTaking the advan tage of high-throughput single nucleotide polymorphism (SNP) genotyping technology, large genome-wide association studies (GWASs) have been considered to hold promise for unravelling complex relationships between genotype and phenotype. At present, traditional single-locus-based methods are insufficient to detect interactions consisting of multiple-locus, which are broadly existing in complex traits. In addition, statistic tests for high order epistatic interactions with more than 2 SNPs propose computational and analytical challenges because the computation increases exponentially as the cardinality of SNPs combinations gets larger.ResultsIn this paper, we provide a simple, fast and powerful method using dynamic clustering and cloud computing to detect genome-wide multi-locus epistatic interactions. We have constructed systematic experiments to compare powers performance against some recently proposed algorithms, including TEAM, SNPRuler, EDCF and BOOST. Furthermore, we have applied our method on two real GWAS datasets, Age-related macular degeneration (AMD) and Rheumatoid arthritis (RA) datasets, where we find some novel potential disease-related genetic factors which are not shown up in detections of 2-loci epistatic interactions.ConclusionsExperimental results on simulated data demonstrate that our method is more powerful than some recently proposed methods on both two- and three-locus disease models. Our method has discovered many novel high-order associations that are significantly enriched in cases from two real GWAS datasets. Moreover, the running time of the cloud implementation for our method on AMD dataset and RA dataset are roughly 2 hours and 50 hours on a cluster with forty small virtual machines for detecting two-locus interactions, respectively. Therefore, we believe that our method is suitable and effective for the full-scale analysis of multiple-locus epistatic interactions in GWAS.

Fast detection of high-order epistatic interactions in genome-wide association studies using information theoretic measure

There are many algorithms for detecting epistatic interactions in GWAS. However, most of these algorithms are applicable only for detecting two-locus interactions. Some algorithms are designed to detect only two-locus interactions from the beginning. Others do not have limits to the order of interactions, but in practice take very long time to detect higher order interactions in real data of GWAS. Even the better ones take days to detect higher order interactions in WTCCC data.We propose a fast algorithm for detection of high order epistatic interactions in GWAS. It runs k-means clustering algorithm on the set of all SNPs. Then candidates are selected from each cluster. These candidates are examined to find the causative SNPs of k-locus interactions. We use mutual information from information theory as the measure of association between genotypes and phenotypes.We tested the power and speed of our method on extensive sets of simulated data. The results show that our method has more or equal power, and runs much faster than previously reported methods. We also applied our algorithm on each of seven diseases in WTCCC data to analyze up to 5-locus interactions. It takes only a few hours to analyze 5-locus interactions in one dataset. From the results we make some interesting and meaningful observations on each disease in WTCCC data.In this study, a simple yet powerful two-step approach is proposed for fast detection of high order epistatic interaction. Our algorithm makes it possible to detect high order epistatic interactions in GWAS in a matter of hours on a PC.

Testing Gene–Gene Interactions in Genome Wide Association Studies

Detection of gene-gene interaction has become increasingly popular over the past decade in genome wide association studies (GWAS). Besides traditional logistic regression analysis for detecting interactions between two markers, new methods have been developed in recent years such as comparing linkage disequilibrium (LD) in case and control groups. All these methods form the building blocks of most screening strategies for disease susceptibility loci in GWAS. In this paper, we are interested in comparing the competing methods and providing practical guidelines for selecting appropriate testing methods for interaction in GWAS. We first review a series of existing statistical methods to detect interactions, and then examine different definitions of interactions to gain insight into the theoretical relationship between the existing testing methods. Lastly, we perform extensive simulations to compare powers of various methods to detect either interaction between two markers at two unlinked loci or the overall association allowing for both interaction and main effects. This investigation reveals informative characteristics of various methods that are helpful to GWAS investigators.

Forward LASSO analysis for high-order interactions in genome-wide association study

Previous genome-wide association study (GWAS) focused on low-order interactions between pairwise single-nucleotide polymorphisms (SNPs) with significant main effects. Little is known how high-order interactions effect, especially one among the SNPs without main effects regulates quantitative traits. Within the frameworks of linear model and generalized linear model, the LASSO with coordinate descent step can be used to simultaneously analyze thousands and thousands of SNPs for normal and discrete traits. With consideration of high-order interactions among SNPs, a huge number of genetic effects make the LASSO failing to work under the presented condition of computation. Forward LASSO analysis is, therefore, proposed to shrink most of genetic effects to be zeros stage by stage. Simulation demonstrates that our proposed method could be used instead of the LASSO method for full model in mapping high-order interactions. Application of forward LASSO method is provided to GWAS for carcass traits and meat quality traits in beef cattle.

Gene-Based Testing of Interactions in Association Studies of Quantitative Traits

Various methods have been developed for identifying gene–gene interactions in genome-wide association studies (GWAS). However, most methods focus on individual markers as the testing unit, and the large number of such tests drastically erodes statistical power. In this study, we propose novel interaction tests of quantitative traits that are gene-based and that confer advantage in both statistical power and biological interpretation. The framework of gene-based gene–gene interaction (GGG) tests combine marker-based interaction tests between all pairs of markers in two genes to produce a gene-level test for interaction between the two. The tests are based on an analytical formula we derive for the correlation between marker-based interaction tests due to linkage disequilibrium. We propose four GGG tests that extend the following P value combining methods: minimum P value, extended Simes procedure, truncated tail strength, and truncated P value product. Extensive simulations point to correct type I error rates of all tests and show that the two truncated tests are more powerful than the other tests in cases of markers involved in the underlying interaction not being directly genotyped and in cases of multiple underlying interactions. We applied our tests to pairs of genes that exhibit a protein–protein interaction to test for gene-level interactions underlying lipid levels using genotype data from the Atherosclerosis Risk in Communities study. We identified five novel interactions that are not evident from marker-based interaction testing and successfully replicated one of these interactions, between SMAD3 and NEDD9, in an independent sample from the Multi-Ethnic Study of Atherosclerosis. We conclude that our GGG tests show improved power to identify gene-level interactions in existing, as well as emerging, association studies.

Abstract IA04: Searching for GxE interactions in genome-wide association studies.

Abstract Although both genetic and environmental factors play important roles in the etiology of many complex human traits, scans for gene(G)-environment(E) interaction have been mostly neglected in current GWAS. This is mainly due to the substantial lack of power for interaction tests coupled with the massive number of interactions available for testing. The conventional statistical approach for interactions, the case-control analysis, suffers from low power. The alternative case-only analysis can be more powerful but slight violations in the underlying assumption of independence can greatly bias the results. In this talk, I discuss several recently proposed alternatives ranging from two-step analyses to Bayesian approaches. Each approach attempts to leverage various aspects of the data, from ascertainment, to marginal test, to estimates of G-E association in the controls. For example, in the two-step approach proposed by Murcray et al. (2009), a preliminary screening step tests the association of G with E in the combined sample of cases and controls, thus capturing any G-E association that may be present in the study sample by leveraging the oversampling of cases from the population. This step is followed by a conventional case-control analysis. Overall, there is a substantial increase in power compared to a genome-wide scan of interactions due to the drastic reduction in the number of tests evaluated. In contrast, several Bayesian approaches (Mukherjee and Chatterjee, 2008; Li and Conti 2009) attempt to obtain an estimate of interaction that is a combined estimate between the case-only and case-control estimates. While originally conceived as an approach for a single GxE interaction test, I will discuss recent extensions leveraging the fact that most SNPs in a GWAS are not associated with either the outcome nor the environmental factor. For these and several other approaches, I will discuss the underlying assumptions and the sensitivity of the performance of each to G-E association in the population, population prevalence, and the assumed causal model. Citation Format: David V. Conti. Searching for GxE interactions in genome-wide association studies. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA04.

Two-stage testing procedures with independent filtering for genome-wide gene-environment interaction

Several two-stage multiple testing procedures have been proposed to detect gene-environment interaction in genome-wide association studies. In this article, we elucidate general conditions that are required for validity and power of these procedures, and we propose extensions of two-stage procedures using the case-only estimator of gene-treatment interaction in randomized clinical trials. We develop a unified estimating equation approach to proving asymptotic independence between a filtering statistic and an interaction test statistic in a range of situations, including marginal association and interaction in a generalized linear model with a canonical link. We assess the performance of various two-stage procedures in simulations and in genetic studies from Women's Health Initiative clinical trials.

BiForce Toolbox: powerful high-throughput computational analysis of gene-gene interactions in genome-wide association studies

Genome-wide association studies (GWAS) have discovered many loci associated with common disease and quantitative traits. However, most GWAS have not studied the gene–gene interactions (epistasis) that could be important in complex trait genetics. A major challenge in analysing epistasis in GWAS is the enormous computational demands of analysing billions of SNP combinations. Several methods have been developed recently to address this, some using computers equipped with particular graphical processing units, most restricted to binary disease traits and all poorly suited to general usage on the most widely used operating systems. We have developed the BiForce Toolbox to address the demand for high-throughput analysis of pairwise epistasis in GWAS of quantitative and disease traits across all commonly used computer systems. BiForce Toolbox is a stand-alone Java program that integrates bitwise computing with multithreaded parallelization and thus allows rapid full pairwise genome scans via a graphical user interface or the command line. Furthermore, BiForce Toolbox incorporates additional tests of interactions involving SNPs with significant marginal effects, potentially increasing the power of detection of epistasis. BiForce Toolbox is easy to use and has been applied in multiple studies of epistasis in large GWAS data sets, identifying interesting interaction signals and pathways.

A novel method to identify high order gene-gene interactions in genome-wide association studies: Gene-based MDR

BackgroundBecause common complex diseases are affected by multiple genes and environmental factors, it is essential to investigate gene-gene and/or gene-environment interactions to understand genetic architecture of complex diseases. After the great success of large scale genome-wide association (GWA) studies using the high density single nucleotide polymorphism (SNP) chips, the study of gene-gene interaction becomes a next challenge. Multifactor dimensionality reduction (MDR) analysis has been widely used for the gene-gene interaction analysis. In practice, however, it is not easy to perform high order gene-gene interaction analyses via MDR in genome-wide level because it requires exploring a huge search space and suffers from a computational burden due to high dimensionality.ResultsWe propose dimensional reduction analysis, Gene-MDR analysis for the fast and efficient high order gene-gene interaction analysis. The proposed Gene-MDR method is composed of two-step applications of MDR: within- and between-gene MDR analyses. First, within-gene MDR analysis summarizes each gene effect via MDR analysis by combining multiple SNPs from the same gene. Second, between-gene MDR analysis then performs interaction analysis using the summarized gene effects from within-gene MDR analysis. We apply the Gene-MDR method to bipolar disorder (BD) GWA data from Wellcome Trust Case Control Consortium (WTCCC). The results demonstrate that Gene-MDR is capable of detecting high order gene-gene interactions associated with BD.ConclusionBy reducing the dimension of genome-wide data from SNP level to gene level, Gene-MDR efficiently identifies high order gene-gene interactions. Therefore, Gene-MDR can provide the key to understand complex disease etiology.