GLIDERS - A web-based search engine for genome-wide linkage disequilibrium between HapMap SNPs
© Lawrence et al; licensee BioMed Central Ltd. 2009
Received: 20 August 2009
Accepted: 31 October 2009
Published: 31 October 2009
A number of tools for the examination of linkage disequilibrium (LD) patterns between nearby alleles exist, but none are available for quickly and easily investigating LD at longer ranges (>500 kb). We have developed a web-based query tool (GLIDERS: Genome-wide LInkage DisEquilibrium Repository and Search engine) that enables the retrieval of pairwise associations with r2 ≥ 0.3 across the human genome for any SNP genotyped within HapMap phase 2 and 3, regardless of distance between the markers.
GLIDERS is an easy to use web tool that only requires the user to enter rs numbers of SNPs they want to retrieve genome-wide LD for (both nearby and long-range). The intuitive web interface handles both manual entry of SNP IDs as well as allowing users to upload files of SNP IDs. The user can limit the resulting inter SNP associations with easy to use menu options. These include MAF limit (5-45%), distance limits between SNPs (minimum and maximum), r2 (0.3 to 1), HapMap population sample (CEU, YRI and JPT+CHB combined) and HapMap build/release. All resulting genome-wide inter-SNP associations are displayed on a single output page, which has a link to a downloadable tab delimited text file.
GLIDERS is a quick and easy way to retrieve genome-wide inter-SNP associations and to explore LD patterns for any number of SNPs of interest. GLIDERS can be useful in identifying SNPs with long-range LD. This can highlight mis-mapping or other potential association signal localisation problems.
The discovery of the block structure of haplotypes has led to much research into patterns of local linkage disequilibrium (LD) in the genome [1–3]. The International HapMap Project was motivated by these discoveries to create a fine-scale catalogue of common single nucleotide polymorphisms (SNPs) in different populations to allow further investigations into LD [4, 5]. The HapMap has allowed researchers to better understand patterns of LD and utilize the information in the design of genome-wide association studies (GWAS). Several tools have been developed allowing researchers to utilize the HapMap data to investigate LD, including Haploview and SNAP [6, 7]. Analysis of HapMap has revealed wide-spread, and often complex, patterns of LD which has made the localization of causal variants difficult in regions identified to be associated with disease through GWAS. Research thus far has been focused on regional patterns of LD and has revealed that LD in most genomic regions decays substantially over several kilobases (Kb) to several hundreds of Kb. Long-range (> 500 Kb) LD has been less well characterized, and at present there are no known resources for researchers to investigate long-range LD. The SNAP server, for example, only allows researchers to investigate markers that are separated by a maximum of 500 Kb. Although regional patterns of LD are indeed very useful, for example in delineating intervals for the follow-up of interesting association signals, it can also be useful to examine patterns of long-range LD. There is a possibility that misplaced SNPs (or potentially epistasis) could produce very long-range cis- (intra-) and even trans- (inter-) chromosomal associations between SNPs. To address the need for a resource investigating long-range LD we have developed the Genome-wide LInkage DisEquilibrium Repository and Search engine (GLIDERS). GLIDERS is a web-based tool allowing researchers to investigate both local and long-range associations between all HapMap phase 2 and 3 SNPs.
Construction and content
HapMap SNPs analyzed for genome-wide LD post-QC.
Utility and Discussion
GLIDERS is an efficient and easy tool allowing researchers to find genome-wide LD between all SNPs investigated in HapMap phase 2 and 3. GLIDERS is not the only tool for interrogating LD in the HapMap data, but it has certain features that set it apart. Firstly, GLIDERS does not require users to download and install software on their local machine, like the popular Haploview program requires. Additionally, GLIDERS has pre-calculated and compiled all the LD information therefore taking the computational burden off the individual researcher. It would also be possible for researchers to perform the same analysis using Haploview by downloading all the phased HapMap genotypes, setting the maximum distance parameter to 0, and exporting the LD values. Then the researcher would have to parse all of that output. Of the available LD resources, SNAP  is the tool that most closely resembles GLIDERS. SNAP is a very good utility but is limited to investigating LD between markers that are a maximum of 500 Kb apart, whereas GLIDERS has an unlimited distance search space. However, because of the greatly expanded distance search space, GLIDERS has an r2 lower bound of 0.3, whereas SNAP has an unlimited r2 search space for SNP associations. Therefore, GLIDERS should be viewed as a complementary tool to SNAP. GLIDERS provides a quick list of potential proxy SNPs and an indication of the extent of LD between the potential proxies and the query SNP(s). GLIDERS also provides insight into potential SNP mapping errors or more interesting biological processes by revealing strong associations between SNPs on different chromosomes. The number of HapMap phase 3 SNPs demonstrating at least one trans-chromosomal association with r2 ≥ 0.3 in the three panel populations are: 17,562 in CEU, 27,064 in YRI, and 1,497 in JPT+CHB. These associations either reveal mapping errors, interesting biology, or that these populations are still young populations that have not had enough time to degrade the LD amongst unlinked loci. Our analysis has also revealed potential data quality issues between HapMap2 and HapMap3, since many of the long-range associations we discovered in the HapMap2 data disappear in HapMap3. This, we believe, is likely to be due to the increased sample size in phase 3 and the removal of poorly performing phase 2 SNPs from phase 3. Therefore we recommend querying your SNPs against HapMap3, with the trade off that there are fewer SNPs analyzed in HapMap3 because of the more stringent QC analysis.
With the large number of GWAS being carried out and the large number of SNPs showing disease association, it is important to be able to check quickly and easily for distant SNP proxies which might affect disease gene localization. GLIDERS is an ideal utility for this as it contains all genome-wide inter-SNP associations between HapMap markers from the three main population samples calculated using both phase 2 and phase 3 genotypes. GLIDERS is an easy to use inter-SNP association web database tool that can be used by any researcher with internet access.
Availability and requirements
The GLIDERS search engine is publicly available at http://www.sanger.ac.uk/Software/GLIDERS. There are no restrictions to the use of GLIDERS by academic or commercial entities.
List of abbreviations
(genome-wide association study)
(minor allele frequency)
(single nucleotide polymorphism)
(Genome-wide LInkage DisEquilibrium Repository and Search engine)
(CEPH (Utah residents with ancestry from northern and western Europe))
(Yoruba in Ibadan, Nigeria)
(Japanese in Tokyo, Japan)
(Han Chinese in Beijing, China)
(Common Gateway Interface)
(SNP Annotation and Proxy Search)
(reference SNP identification)
The authors thank Tim Bardsley, Ruth Porter and Mark Gibbons for IT support.
This work was funded by the Wellcome Trust (088885/Z/09/Z and 079557MA).
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