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1.  GSA-SNP: a general approach for gene set analysis of polymorphisms 
Nucleic Acids Research  2010;38(Web Server issue):W749-W754.
Genome-wide association (GWA) study aims to identify the genetic factors associated with the traits of interest. However, the power of GWA analysis has been seriously limited by the enormous number of markers tested. Recently, the gene set analysis (GSA) methods were introduced to GWA studies to address the association of gene sets that share common biological functions. GSA considerably increased the power of association analysis and successfully identified coordinated association patterns of gene sets. There have been several approaches in this direction with some limitations. Here, we present a general approach for GSA in GWA analysis and a stand-alone software GSA-SNP that implements three widely used GSA methods. GSA-SNP provides a fast computation and an easy-to-use interface. The software and test datasets are freely available at http://gsa.muldas.org. We provide an exemplary analysis on adult heights in a Korean population.
doi:10.1093/nar/gkq428
PMCID: PMC2896081  PMID: 20501604
2.  Gene set analysis of survival following ovarian cancer implicates macrolide binding and intracellular signaling genes 
Background
Genome-wide association studies (GWAS) for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy, have identified novel susceptibility loci. GWAS for survival after EOC have had more limited success. The association of each single nucleotide polymorphism (SNP) individually may not be well-suited to detect small effects of multiple SNPs, such as those operating within the same biological pathway. Gene set analysis (GSA) overcomes this limitation by assessing overall evidence for association of a phenotype with all measured variation in a set of genes.
Methods
To determine gene sets associated with EOC overall survival, we conducted GSA using data from two large GWASes (N cases = 2,813, N deaths = 1,116), with a novel Principal Component – Gamma GSA method. Analysis was completed for all cases and then separately for high grade serous (HGS) histological subtype.
Results
Analysis of the HGS subjects resulted in 43 gene sets with p<0.005 (1.7%); of these, 21 gene sets had p < 0.10 in both GWASes, including intracellular signaling pathway (p = 7.3 × 10−5) and macrolide binding (p = 6.2 ×10−4) gene sets. The top gene sets in analysis of all cases were meiotic mismatch repair (p=6.3 ×10−4) and macrolide binding (p=1.0×10−3). Of 18 gene sets with p<0.005 (0.7%), eight had p < 0.10 in both GWASes.
Conclusion
This research detected novel gene sets associated with EOC survival.
Impact
Novel gene sets associated with EOC survival might lead to new insights and avenues for development of novel therapies for EOC and pharmacogenomic studies.
doi:10.1158/1055-9965.EPI-11-0741
PMCID: PMC3297690  PMID: 22302016
pathway analysis; genetic association; GWAS; SNPs; gynecologic neoplasm
3.  Network-Assisted Investigation of Combined Causal Signals from Genome-Wide Association Studies in Schizophrenia 
PLoS Computational Biology  2012;8(7):e1002587.
With the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each single GWAS dataset and then implemented a discovery-evaluation strategy to identify module genes with consistent association signals. We validated the module genes in an independent dataset, and also examined them through meta-analysis of the related SNPs using multiple GWAS datasets. As a result, we identified 205 module genes with a joint effect significantly associated with schizophrenia; these module genes included a number of well-studied candidate genes such as DISC1, GNA12, GNA13, GNAI1, GPR17, and GRIN2B. Further functional analysis suggested these genes are involved in neuronal related processes. Additionally, meta-analysis found that 18 SNPs in 9 module genes had Pmeta<1×10−4, including the gene HLA-DQA1 located in the MHC region on chromosome 6, which was reported in previous studies using the largest cohort of schizophrenia patients to date. These results demonstrated our bi-directional network-based strategy is efficient for identifying disease-associated genes with modest signals in GWAS datasets. This approach can be applied to any other complex diseases/traits where multiple GWAS datasets are available.
Author Summary
The recent success of genome-wide association studies (GWAS) has generated a wealth of genotyping data critical to studies of genetic architectures of many complex diseases. In contrast to traditional single marker analysis, an integrative analysis of multiple genes and the assessment of their joint effects have been particularly promising, especially upon the availability of many GWAS datasets and other high-throughput datasets for numerous complex diseases. In this study, we developed an integrative analysis framework for multiple GWAS datasets and demonstrated it in schizophrenia. We first constructed a GWAS-weighted protein-protein interaction (PPI) network and then applied a dense module search algorithm to identify subnetworks with combinatory disease effects. We applied combinatorial criteria for module selection based on permutation tests to determine whether the modules are significantly different from random gene sets and whether the modules are associated with the disease in investigation. Importantly, considering there are many complex diseases with multiple GWAS datasets available, we proposed a discovery-evaluation strategy to search for modules with consistent combined effects from two or more GWAS datasets. This approach can be applied to any diseases or traits that have two or more GWAS datasets available.
doi:10.1371/journal.pcbi.1002587
PMCID: PMC3390381  PMID: 22792057
4.  Using Biological Knowledge to Uncover the Mystery in the Search for Epistasis in Genome-Wide Association Studies 
Annals of human genetics  2011;75(1):172-182.
The search for the missing heritability in genome-wide association studies (GWAS) has become an important focus for the human genetics community. One suspected location of these genetic effects is in gene-gene interactions, or epistasis. The computational burden of exploring gene-gene interactions in the wealth of data generated in GWAS, along with small to moderate sample sizes, have led to epistasis being an afterthought, rather than a primary focus of GWAS analyses. In this review, we discuss some potential approaches to filter a GWAS dataset to a smaller, more manageable dataset where searching for epistasis is considerably more feasible. We describe a number of alternative approaches, but primarily focus on the use of prior biological knowledge from databases in the public domain to guide the search for epistasis. The manner in which prior knowledge is incorporated into a GWA study can be many and these data can be extracted from a variety of database sources. We discuss a number of these approaches and propose that a comprehensive approach will likely be most fruitful for searching for epistasis in large-scale genomic studies of the current state-of-the-art and into the future.
doi:10.1111/j.1469-1809.2010.00630.x
PMCID: PMC3092784  PMID: 21158748
epistasis; prior knowledge; pathways; protein-protein interactions; gene-gene interactions
5.  Using prior knowledge and genome-wide association to identify pathways involved in multiple sclerosis 
Genome Medicine  2009;1(6):65.
The efforts of the Human Genome Project are beginning to provide important findings for human health. Technological advances in the laboratory, particularly in characterizing human genomic variation, have created new approaches for studying the human genome - genome-wide association studies (GWAS). However, current statistical and computational strategies are taking only partial advantage of this wealth of information. In the quest for susceptibility genes for complex diseases in GWAS data, several different analytic strategies are being pursued. In a recent report, Baranzini and colleagues used a pathway- and network-based analysis to explore potentially interesting single locus association signals in a GWAS of multiple sclerosis. This and other pathway-based approaches are likely to continue to emerge in the GWAS literature, as they provide a powerful strategy to detect important modest single-locus effects and gene-gene interaction effects.
doi:10.1186/gm65
PMCID: PMC2703874  PMID: 19566917
6.  Network-assisted Causal Gene Detection in Genome-wide Association Studies: An Improved Module Search Algorithm 
The recent success of genome-wide association (GWA) studies has greatly expanded our understanding of many complex diseases by delivering previously unknown loci and genes. A large number of GWAS datasets have already been made available, with more being generated. To explore the underlying moderate and weak signals, we recently developed a network-based dense module search (DMS) method for identification of disease candidate genes from GWAS datasets, leveraging on the joint effect of multiple genes. DMS is designed to dynamically search for the best nodes in a step-wise fashion and, thus, could overcome the limitation of pre-defined gene sets. Here, we propose an improved version of DMS, the topologically-adjusted DMS, to facilitate the analysis of complex diseases. Building on the previous version of DMS, we improved the randomization process by taking into account the topological character, aiming to adjust the bias potentially caused by high-degree nodes in the whole network. We demonstrated the topologically-adjusted DMS algorithm in a GWAS dataset for schizophrenia. We found the improved DMS strategy could effectively identify candidate genes while reducing the burden of high-degree nodes. In our evaluation, we found more candidate genes identified by the topologically-adjusted DMS algorithm have been reported in the previous association studies, suggesting this new algorithm has better performance than the unweighted DMS algorithm. Finally, our functional analysis of the top module genes revealed that they are enriched in immune-related pathways.
doi:10.1109/GENSiPS.2011.6169462
PMCID: PMC3418601  PMID: 22898890
dmGWAS; dense module search; GWAS; schizophrenia; network; gene set enrichment analysis
7.  dmGWAS: dense module searching for genome-wide association studies in protein–protein interaction networks 
Bioinformatics  2010;27(1):95-102.
Motivation: An important question that has emerged from the recent success of genome-wide association studies (GWAS) is how to detect genetic signals beyond single markers/genes in order to explore their combined effects on mediating complex diseases and traits. Integrative testing of GWAS association data with that from prior-knowledge databases and proteome studies has recently gained attention. These methodologies may hold promise for comprehensively examining the interactions between genes underlying the pathogenesis of complex diseases.
Methods: Here, we present a dense module searching (DMS) method to identify candidate subnetworks or genes for complex diseases by integrating the association signal from GWAS datasets into the human protein–protein interaction (PPI) network. The DMS method extensively searches for subnetworks enriched with low P-value genes in GWAS datasets. Compared with pathway-based approaches, this method introduces flexibility in defining a gene set and can effectively utilize local PPI information.
Results: We implemented the DMS method in an R package, which can also evaluate and graphically represent the results. We demonstrated DMS in two GWAS datasets for complex diseases, i.e. breast cancer and pancreatic cancer. For each disease, the DMS method successfully identified a set of significant modules and candidate genes, including some well-studied genes not detected in the single-marker analysis of GWA studies. Functional enrichment analysis and comparison with previously published methods showed that the genes we identified by DMS have higher association signal.
Availability: dmGWAS package and documents are available at http://bioinfo.mc.vanderbilt.edu/dmGWAS.html.
Contact: zhongming.zhao@vanderbilt.edu
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq615
PMCID: PMC3008643  PMID: 21045073
8.  Performance Comparison of Two Gene Set Analysis Methods for Genome-wide Association Study Results: GSA-SNP vs i-GSEA4GWAS 
Genomics & Informatics  2012;10(2):123-127.
Gene set analysis (GSA) is useful in interpreting a genome-wide association study (GWAS) result in terms of biological mechanism. We compared the performance of two different GSA implementations that accept GWAS p-values of single nucleotide polymorphisms (SNPs) or gene-by-gene summaries thereof, GSA-SNP and i-GSEA4GWAS, under the same settings of inputs and parameters. GSA runs were made with two sets of p-values from a Korean type 2 diabetes mellitus GWAS study: 259,188 and 1,152,947 SNPs of the original and imputed genotype datasets, respectively. When Gene Ontology terms were used as gene sets, i-GSEA4GWAS produced 283 and 1,070 hits for the unimputed and imputed datasets, respectively. On the other hand, GSA-SNP reported 94 and 38 hits, respectively, for both datasets. Similar, but to a lesser degree, trends were observed with Kyoto Encyclopedia of Genes and Genomes (KEGG) gene sets as well. The huge number of hits by i-GSEA4GWAS for the imputed dataset was probably an artifact due to the scaling step in the algorithm. The decrease in hits by GSA-SNP for the imputed dataset may be due to the fact that it relies on Z-statistics, which is sensitive to variations in the background level of associations. Judicious evaluation of the GSA outcomes, perhaps based on multiple programs, is recommended.
doi:10.5808/GI.2012.10.2.123
PMCID: PMC3480679  PMID: 23105940
gene set analysis; genome-wide association study; GSA-SNP; i-GSEA4GWAS; imputation
9.  Enriching the gene set analysis of genome-wide data by incorporating directionality of gene expression and combining statistical hypotheses and methods 
Nucleic Acids Research  2013;41(8):4378-4391.
Gene set analysis (GSA) is used to elucidate genome-wide data, in particular transcriptome data. A multitude of methods have been proposed for this step of the analysis, and many of them have been compared and evaluated. Unfortunately, there is no consolidated opinion regarding what methods should be preferred, and the variety of available GSA software and implementations pose a difficulty for the end-user who wants to try out different methods. To address this, we have developed the R package Piano that collects a range of GSA methods into the same system, for the benefit of the end-user. Further on we refine the GSA workflow by using modifications of the gene-level statistics. This enables us to divide the resulting gene set P-values into three classes, describing different aspects of gene expression directionality at gene set level. We use our fully implemented workflow to investigate the impact of the individual components of GSA by using microarray and RNA-seq data. The results show that the evaluated methods are globally similar and the major separation correlates well with our defined directionality classes. As a consequence of this, we suggest to use a consensus scoring approach, based on multiple GSA runs. In combination with the directionality classes, this constitutes a more thorough basis for an enriched biological interpretation.
doi:10.1093/nar/gkt111
PMCID: PMC3632109  PMID: 23444143
10.  An empirical evaluation of imputation accuracy for association statistics reveals increased type-I error rates in genome-wide associations 
BMC Genetics  2011;12:10.
Background
Genome wide association studies (GWAS) are becoming the approach of choice to identify genetic determinants of complex phenotypes and common diseases. The astonishing amount of generated data and the use of distinct genotyping platforms with variable genomic coverage are still analytical challenges. Imputation algorithms combine directly genotyped markers information with haplotypic structure for the population of interest for the inference of a badly genotyped or missing marker and are considered a near zero cost approach to allow the comparison and combination of data generated in different studies. Several reports stated that imputed markers have an overall acceptable accuracy but no published report has performed a pair wise comparison of imputed and empiric association statistics of a complete set of GWAS markers.
Results
In this report we identified a total of 73 imputed markers that yielded a nominally statistically significant association at P < 10 -5 for type 2 Diabetes Mellitus and compared them with results obtained based on empirical allelic frequencies. Interestingly, despite their overall high correlation, association statistics based on imputed frequencies were discordant in 35 of the 73 (47%) associated markers, considerably inflating the type I error rate of imputed markers. We comprehensively tested several quality thresholds, the haplotypic structure underlying imputed markers and the use of flanking markers as predictors of inaccurate association statistics derived from imputed markers.
Conclusions
Our results suggest that association statistics from imputed markers showing specific MAF (Minor Allele Frequencies) range, located in weak linkage disequilibrium blocks or strongly deviating from local patterns of association are prone to have inflated false positive association signals. The present study highlights the potential of imputation procedures and proposes simple procedures for selecting the best imputed markers for follow-up genotyping studies.
doi:10.1186/1471-2156-12-10
PMCID: PMC3224203  PMID: 21251252
11.  The power of regional heritability analysis for rare and common variant detection: simulations and application to eye biometrical traits 
Frontiers in Genetics  2013;4:232.
Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of complex traits. However, they have explained relatively little trait heritability. Recently, we proposed a new analytical approach called regional heritability mapping (RHM) that captures more of the missing genetic variation. This method is applicable both to related and unrelated populations. Here, we demonstrate the power of RHM in comparison with single-SNP GWAS and gene-based association approaches under a wide range of scenarios with variable numbers of quantitative trait loci (QTL) with common and rare causal variants in a narrow genomic region. Simulations based on real genotype data were performed to assess power to capture QTL variance, and we demonstrate that RHM has greater power to detect rare variants and/or multiple alleles in a region than other approaches. In addition, we show that RHM can capture more accurately the QTL variance, when it is caused by multiple independent effects and/or rare variants. We applied RHM to analyze three biometrical eye traits for which single-SNP GWAS have been published or performed to evaluate the effectiveness of this method in real data analysis and detected some additional loci which were not detected by other GWAS methods. RHM has the potential to explain some of missing heritability by capturing variance caused by QTL with low MAF and multiple independent QTL in a region, not captured by other GWAS methods. RHM analyses can be implemented using the software REACTA (http://www.epcc.ed.ac.uk/projects-portfolio/reacta).
doi:10.3389/fgene.2013.00232
PMCID: PMC3832942  PMID: 24312116
common and rare variants; GWAS; regional heritability mapping; multiple independent effects; missing heritability
12.  Systems Genetics: A Novel Approach to Dissect the Genetic Basis of Osteoporosis 
Current osteoporosis reports  2012;10(3):228-235.
From the early 1990s to the middle of the last decade, the search for genes influencing osteoporosis proved difficult with few successes. However, over the last 5 years this has begun to change with the introduction of genome-wide association (GWA) studies. In this short period of time, GWA studies have significantly accelerated the pace of gene discovery, leading to the identification of nearly 100 independent associations for osteoporosis-related traits. However, GWA does not specifically pinpoint causal genes or provide functional context for associations. Thus, there is a need for approaches that provide systems-level insight on how associated variants influence cellular function, downstream gene networks, and ultimately disease. In this review we discuss the emerging field of “systems genetics” and how it is being used in combination with and independent of GWA to improve our understanding of the molecular mechanisms involved in bone fragility.
doi:10.1007/s11914-012-0112-5
PMCID: PMC3422742  PMID: 22802146
Systems genetics; Systems biology; Coexpression network; Causality modeling; Genetics of osteoporosis; Genome-wide association study
13.  Prediction of Disease and Phenotype Associations from Genome-Wide Association Studies 
PLoS ONE  2011;6(11):e27175.
Background
Genome wide association studies (GWAS) have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP). The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases.
Methodology/Principal Findings
Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD) and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs) were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits.
Conclusions/Significance
The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.
doi:10.1371/journal.pone.0027175
PMCID: PMC3208586  PMID: 22076134
14.  Gene set analysis of SNP data: benefits, challenges, and future directions 
The last decade of human genetic research witnessed the completion of hundreds of genome-wide association studies (GWASs). However, the genetic variants discovered through these efforts account for only a small proportion of the heritability of complex traits. One explanation for the missing heritability is that the common analysis approach, assessing the effect of each single-nucleotide polymorphism (SNP) individually, is not well suited to the detection of small effects of multiple SNPs. Gene set analysis (GSA) is one of several approaches that may contribute to the discovery of additional genetic risk factors for complex traits. Complex phenotypes are thought to be controlled by networks of interacting biochemical and physiological pathways influenced by the products of sets of genes. By assessing the overall evidence of association of a phenotype with all measured variation in a set of genes, GSA may identify functionally relevant sets of genes corresponding to relevant biomolecular pathways, which will enable more focused studies of genetic risk factors. This approach may thus contribute to the discovery of genetic variants responsible for some of the missing heritability. With the increased use of these approaches for the secondary analysis of data from GWAS, it is important to understand the different GSA methods and their strengths and weaknesses, and consider challenges inherent in these types of analyses. This paper provides an overview of GSA, highlighting the key challenges, potential solutions, and directions for ongoing research.
doi:10.1038/ejhg.2011.57
PMCID: PMC3172936  PMID: 21487444
pathway analysis; multilocus; complex traits; genetic association studies
15.  The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes 
Human Molecular Genetics  2012;21(9):2111-2123.
Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the ‘missing heritability problem’. Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complimentary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility as well as novel candidate genes enriched for functions related to T cell receptor signaling and adenosine triphosphate synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility.
doi:10.1093/hmg/dds021
PMCID: PMC3315207  PMID: 22286170
16.  Genome-Wide Gene Set Analysis for Identification of Pathways Associated with Alcohol Dependence 
It is believed that multiple genetic variants with small individual effects contribute to the risk of alcohol dependence. Such polygenic effects are difficult to detect in genome-wide association studies that test for association of the phenotype with each single nucleotide polymorphism (SNP) individually. To overcome this challenge, gene set analysis (GSA) methods that jointly test for the effects of pre-defined groups of genes have been proposed. Rather than testing for association between the phenotype and individual SNPs, these analyses evaluate the global evidence of association with a set of related genes enabling the identification of cellular or molecular pathways or biological processes that play a role in development of the disease. It is hoped that by aggregating the evidence of association for all available SNPs in a group of related genes, these approaches will have enhanced power to detect genetic associations with complex traits. We performed GSA using data from a genome-wide study of 1165 alcohol dependent cases and 1379 controls from the Study of Addiction: Genetics and Environment (SAGE), for all 200 pathways listed in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results demonstrated a potential role of the “Synthesis and Degradation of Ketone Bodies” pathway. Our results also support the potential involvement of the “Neuroactive Ligand Receptor Interaction” pathway, which has previously been implicated in addictive disorders. These findings demonstrate the utility of GSA in the study of complex disease, and suggest specific directions for further research into the genetic architecture of alcohol dependence.
doi:10.1017/S1461145712000375
PMCID: PMC3854955  PMID: 22717047
pathway; gene set analysis; alcohol dependence; alcoholism; ketone bodies; neuroactive ligand receptors
17.  Pathway-Based Genetic Analysis of Preterm Birth 
Genomics  2013;101(3):163-170.
Preterm birth in the United States is now 12%. Multiple genes, gene networks, variants have been associated with this disease. Using a custom database for preterm birth (dbPTB) with a refined set of genes extensively curated from literature and biological databases, we analyzed a GWAS of preterm birth for complete genotype data on nearly 2000 preterm and term mothers. We used both the curated genes and a genome-wide approach to carry out a pathway-based analysis. There were 19 significant pathways, which withstood FDR correction for multiple testing that were identified using both the curated genes and the genome-wide approach. The analysis based on the curated genes was more significant than genome-wide in 15 out of 19 pathways. This approach demonstrates the use of a validated set of genes, in the analysis of otherwise unsuccessful GWAS data, to identify gene-gene interactions in a way that enhances statistical power and discovery.
doi:10.1016/j.ygeno.2012.12.005
PMCID: PMC3570639  PMID: 23298525
Preterm birth; Pathway analysis; GWAS
18.  Integration of biological networks and pathways with genetic association studies 
Human genetics  2012;131(10):1677-1686.
Millions of genetic variants have been assessed for their effects on the trait of interest in genome-wide association studies (GWAS). The complex traits are affected by a set of inter-related genes. However, the typical GWAS only examine the association of a single genetic variant at a time. The individual effects of a complex trait are usually small, and the simple sum of these individual effects may not reflect the holistic effect of the genetic system. High-throughput methods enable genomic studies to produce a large amount of data to expand the knowledge base of the biological systems. Biological networks and pathways are built to represent the functional or physical connectivity among genes. Integrated with GWAS data, the network- and pathway-based methods complement the approach of single genetic variant analysis, and may improve the power to identify trait-associated genes. Taking advantage of the biological knowledge, these approaches are valuable to interpret the functional role of the genetic variants, and to further understand the molecular mechanism influencing the traits. The network- and pathway-based methods have demonstrated their utilities, and will be increasingly important to address a number of challenges facing the mainstream GWAS.
doi:10.1007/s00439-012-1198-7
PMCID: PMC3432693  PMID: 22777728
19.  Analysis of genome-wide association study data using the protein knowledge base 
BMC Genetics  2011;12:98.
Background
Genome-wide association studies (GWAS) aim to identify causal variants and genes for complex disease by independently testing a large number of SNP markers for disease association. Although genes have been implicated in these studies, few utilise the multiple-hit model of complex disease to identify causal candidates. A major benefit of multi-locus comparison is that it compensates for some shortcomings of current statistical analyses that test the frequency of each SNP in isolation for the phenotype population versus control.
Results
Here we developed and benchmarked several protocols for GWAS data analysis using different in-silico gene prediction and prioritisation methodologies. We adopted a high sensitivity approach to the data, using less conservative statistical SNP associations. Multiple gene search spaces, either of fixed-widths or proximity-based, were generated around each SNP marker. We used the candidate disease gene prediction system Gentrepid to identify candidates based on shared biomolecular pathways or domain-based protein homology. Predictions were made either with phenotype-specific known disease genes as input; or without a priori knowledge, by exhaustive comparison of genes in distinct loci. Because Gentrepid uses biomolecular data to find interactions and common features between genes in distinct loci of the search spaces, it takes advantage of the multi-locus aspect of the data.
Conclusions
Results suggest testing multiple SNP-to-gene search spaces compensates for differences in phenotypes, populations and SNP platforms. Surprisingly, domain-based homology information was more informative when benchmarked against gene candidates reported by GWA studies compared to previously determined disease genes, possibly suggesting a larger contribution of gene homologs to complex diseases than Mendelian diseases.
doi:10.1186/1471-2156-12-98
PMCID: PMC3261104  PMID: 22077927
20.  Gene, pathway and network frameworks to identify epistatic interactions of single nucleotide polymorphisms derived from GWAS data 
BMC Systems Biology  2012;6(Suppl 3):S15.
Background
Interactions among genomic loci (also known as epistasis) have been suggested as one of the potential sources of missing heritability in single locus analysis of genome-wide association studies (GWAS). The computational burden of searching for interactions is compounded by the extremely low threshold for identifying significant p-values due to multiple hypothesis testing corrections. Utilizing prior biological knowledge to restrict the set of candidate SNP pairs to be tested can alleviate this problem, but systematic studies that investigate the relative merits of integrating different biological frameworks and GWAS data have not been conducted.
Results
We developed four biologically based frameworks to identify pairwise interactions among candidate SNP pairs as follows: (1) for each human protein-coding gene, a set of SNPs associated with that gene was constructed providing a gene-based interaction model, (2) for each known biological pathway, a set of SNPs associated with the genes in the pathway was constructed providing a pathway-based interaction model, (3) a set of SNPs associated with genes in a disease-related subnetwork provides a network-based interaction model, and (4) a framework is based on the function of SNPs. The last approach uses expression SNPs (eSNPs or eQTLs), which are SNPs or loci that have defined effects on the abundance of transcripts of other genes. We constructed pairs of eSNPs and SNPs located in the target genes whose expression is regulated by eSNPs. For all four frameworks the SNP sets were exhaustively tested for pairwise interactions within the sets using a traditional logistic regression model after excluding genes that were previously identified to associate with the trait. Using previously published GWAS data for type 2 diabetes (T2D) and the biologically based pair-wise interaction modeling, we identify twelve genes not seen in the previous single locus analysis.
Conclusion
We present four approaches to detect interactions associated with complex diseases. The results show our approaches outperform the traditional single locus approaches in detecting genes that previously did not reach significance; the results also provide novel drug targets and biomarkers relevant to the underlying mechanisms of disease.
doi:10.1186/1752-0509-6-S3-S15
PMCID: PMC3524014  PMID: 23281810
21.  A novel variational Bayes multiple locus Z-statistic for genome-wide association studies with Bayesian model averaging 
Bioinformatics  2012;28(13):1738-1744.
Motivation: For many complex traits, including height, the majority of variants identified by genome-wide association studies (GWAS) have small effects, leaving a significant proportion of the heritable variation unexplained. Although many penalized multiple regression methodologies have been proposed to increase the power to detect associations for complex genetic architectures, they generally lack mechanisms for false-positive control and diagnostics for model over-fitting. Our methodology is the first penalized multiple regression approach that explicitly controls Type I error rates and provide model over-fitting diagnostics through a novel normally distributed statistic defined for every marker within the GWAS, based on results from a variational Bayes spike regression algorithm.
Results: We compare the performance of our method to the lasso and single marker analysis on simulated data and demonstrate that our approach has superior performance in terms of power and Type I error control. In addition, using the Women's Health Initiative (WHI) SNP Health Association Resource (SHARe) GWAS of African-Americans, we show that our method has power to detect additional novel associations with body height. These findings replicate by reaching a stringent cutoff of marginal association in a larger cohort.
Availability: An R-package, including an implementation of our variational Bayes spike regression (vBsr) algorithm, is available at http://kooperberg.fhcrc.org/soft.html.
Contact: blogsdon@fhcrc.org
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts261
PMCID: PMC3381972  PMID: 22563072
22.  Quality Control Procedures for Genome Wide Association Studies 
Genome-wide association studies (GWAS) are being conducted at an unprecedented rate in population-based cohorts and have increased our understanding of the pathophysiology of complex disease. The recent application of GWAS to clinic-based cohorts has also yielded genetic predictors of clinical outcomes. Regardless of context, the practical utility of this information will ultimately depend upon the quality of the original data. Quality control (QC) procedures for GWAS are computationally intensive, operationally challenging, and constantly evolving. With each new dataset, new realities are discovered about GWAS data and best practices continue to be developed. The Genomics Workgroup of the National Human Genome Research Institute (NHGRI) funded electronic Medical Records and Genomics (eMERGE) network has invested considerable effort in developing strategies for QC of these data. The lessons learned by this group will be valuable for other investigators dealing with large scale genomic datasets. Here we enumerate some of the challenges in QC of GWAS data and describe the approaches that the eMERGE network is using for quality assurance in GWAS data, thereby minimizing potential bias and error in GWAS results. In this protocol we discuss common issues associated with QC of GWAS data, including data file formats, software packages for data manipulation and analysis, sex chromosome anomalies, sample identity, sample relatedness, population substructure, batch effects, and marker quality. We propose best practices and discuss areas of ongoing and future research.
doi:10.1002/0471142905.hg0119s68
PMCID: PMC3066182  PMID: 21234875
23.  GAGE: generally applicable gene set enrichment for pathway analysis 
BMC Bioinformatics  2009;10:161.
Background
Gene set analysis (GSA) is a widely used strategy for gene expression data analysis based on pathway knowledge. GSA focuses on sets of related genes and has established major advantages over individual gene analyses, including greater robustness, sensitivity and biological relevance. However, previous GSA methods have limited usage as they cannot handle datasets of different sample sizes or experimental designs.
Results
To address these limitations, we present a new GSA method called Generally Applicable Gene-set Enrichment (GAGE). We successfully apply GAGE to multiple microarray datasets with different sample sizes, experimental designs and profiling techniques. GAGE shows significantly better results when compared to two other commonly used GSA methods of GSEA and PAGE. We demonstrate this improvement in the following three aspects: (1) consistency across repeated studies/experiments; (2) sensitivity and specificity; (3) biological relevance of the regulatory mechanisms inferred.
GAGE reveals novel and relevant regulatory mechanisms from both published and previously unpublished microarray studies. From two published lung cancer data sets, GAGE derived a more cohesive and predictive mechanistic scheme underlying lung cancer progress and metastasis. For a previously unpublished BMP6 study, GAGE predicted novel regulatory mechanisms for BMP6 induced osteoblast differentiation, including the canonical BMP-TGF beta signaling, JAK-STAT signaling, Wnt signaling, and estrogen signaling pathways–all of which are supported by the experimental literature.
Conclusion
GAGE is generally applicable to gene expression datasets with different sample sizes and experimental designs. GAGE consistently outperformed two most frequently used GSA methods and inferred statistically and biologically more relevant regulatory pathways. The GAGE method is implemented in R in the "gage" package, available under the GNU GPL from .
doi:10.1186/1471-2105-10-161
PMCID: PMC2696452  PMID: 19473525
24.  A Network-Based Approach to Prioritize Results from Genome-Wide Association Studies 
PLoS ONE  2011;6(9):e24220.
Genome-wide association studies (GWAS) are a valuable approach to understanding the genetic basis of complex traits. One of the challenges of GWAS is the translation of genetic association results into biological hypotheses suitable for further investigation in the laboratory. To address this challenge, we introduce Network Interface Miner for Multigenic Interactions (NIMMI), a network-based method that combines GWAS data with human protein-protein interaction data (PPI). NIMMI builds biological networks weighted by connectivity, which is estimated by use of a modification of the Google PageRank algorithm. These weights are then combined with genetic association p-values derived from GWAS, producing what we call ‘trait prioritized sub-networks.’ As a proof of principle, NIMMI was tested on three GWAS datasets previously analyzed for height, a classical polygenic trait. Despite differences in sample size and ancestry, NIMMI captured 95% of the known height associated genes within the top 20% of ranked sub-networks, far better than what could be achieved by a single-locus approach. The top 2% of NIMMI height-prioritized sub-networks were significantly enriched for genes involved in transcription, signal transduction, transport, and gene expression, as well as nucleic acid, phosphate, protein, and zinc metabolism. All of these sub-networks were ranked near the top across all three height GWAS datasets we tested. We also tested NIMMI on a categorical phenotype, Crohn’s disease. NIMMI prioritized sub-networks involved in B- and T-cell receptor, chemokine, interleukin, and other pathways consistent with the known autoimmune nature of Crohn’s disease. NIMMI is a simple, user-friendly, open-source software tool that efficiently combines genetic association data with biological networks, translating GWAS findings into biological hypotheses.
doi:10.1371/journal.pone.0024220
PMCID: PMC3168369  PMID: 21915301
25.  Genome-Wide Association Study of Coronary Artery Disease 
Coronary artery disease (CAD) is a multifactorial disease with environmental and genetic determinants. The genetic determinants of CAD have previously been explored by the candidate gene approach. Recently, the data from the International HapMap Project and the development of dense genotyping chips have enabled us to perform genome-wide association studies (GWAS) on a large number of subjects without bias towards any particular candidate genes. In 2007, three chip-based GWAS simultaneously revealed the significant association between common variants on chromosome 9p21 and CAD. This association was replicated among other ethnic groups and also in a meta-analysis. Further investigations have detected several other candidate loci associated with CAD. The chip-based GWAS approach has identified novel and unbiased genetic determinants of CAD and these insights provide the important direction to better understand the pathogenesis of CAD and to develop new and improved preventive measures and treatments for CAD.
doi:10.4061/2010/790539
PMCID: PMC2958466  PMID: 20981302

Results 1-25 (1117199)