BOSTON UNIVERSITY SCHOOL OF MEDICINEdepartment of genetics & genomicsGMED
Associations from the FHS Offspring Cohort 100K Scan
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About the FHS Offspring Cohort 100K Genome Scan
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GMED Website Information

candidate associations

The primary purpose of GMED is to rapidly disseminate information about the candidate associations we've uncovered so that they can be tested for replication in other populations. GMED will be updated with new information concerning both positive and negative replication studies.

While many genetic associations of common variants have been reported for a number of traits, remarkably few are robust to replication. Recent meta-analysis of 25 reported genetic associations with complex diseases showed that fewer than half have replicated in follow up studies and >95% have not consistently replicated [Hirschhorn et al., 2002], owing to the confounding effects of population stratification, sample ascertainment and other factors. The lack of consistent replication makes it challenging to interpret the more than 70 reported associations between body mass index and common genetic variants identified through candidate gene studies [Perusse et al., 2005].

public access

GMED also serves to make the results from our genome scan accessible to the broader scientific and medical communities. We hope this will serve to generate new insights into the possible biological and clinical ramifications of the associations we've uncovered.

technologies used

The GMED website utilizes a number of open source software projects. Two genomics-specific projects that helped us deploy GMED rapidly are Flash GViewer by Simon Twigger and GBrowse. Flash Gviewer is used to plot associations on a map of human chromosomes in the Phenotype Browser. GBrowse is used for the Genome Browser portion of the website and also generates the genomic region overview for the Association Details pages.

site overview

the website provides functionality to find candidate associations using either phenotype-centric or genomic-region-centric searching strategies. Genomic-region-centric searching functionality (e.g. searching for a specific gene, cytoband, or sequence interval) is provided through an installation of the GMOD Genome Browser [Stein et al., 2002]. This genome browser has been populated with information from the UCSC annotations (build 17) [Karolchik et al., 2003] of the NCBI Build 35 human genome sequence. The genome browser database is also populated with the results from each of our association analyses such that searching for a landmark allows one to see any nearby associations. The phenotype-centric searching functionality is provided through the Phenotype Browser.

page specific help

Phenotype Browser. Instructions for using the phenotype browser are provided in an orange box to the right of the phenotype browser.

Association Details. This page is divided into two main sections. An example of the Genomic Context / SNP Details portion of the page is provided in the figure below. The numbered items in the figure correspond to the numbered items in this text. This portion of the page provides information about the SNP (including the Affymetrix SNP ID -- 1) and the dbSNP ID -- 2), its location in the genome (3) (including nearby genes -- 4), the alleles (5) and the frequencies of these alleles from the HapMap project genotyping (7).

Several details should be kept in mind when using the information on the Association Details page. First, the genomic coordinates for each SNP are based on the NCBI Build 35 sequence of the human genome and incorporate annotation information from version HG17 of the UCSC annotation tracks. Second, the alleles reported for "Allele 1" and "Allele 2" are the allele designations used by Affymetrix. In some cases, these alleles may be on the opposite strand of what is reported in HapMap (for example compare 6 and 7). This can be especially confusing for SNPs that have arisen through transversion (i.e. changes from A/T to T/A or G/C to C/G). The allele frequency graph uses the allele designations from HapMap. The phenotype x genotype graph uses the Affymetrix alleles.

Additional information about the region surrounding each SNP can be found by clicking on the coordinate axis in the genomic region image. This opens the region in the Genome Browser. The genome browser can be used to find other associations identified in the region as well as information about refseq transcripts and the locations of other nearby SNPs typed as part of the project. The genome browser can also be used to view information for either a larger or smaller window surrounding the associated SNP. Additional information about the genes in the region can be found by clicking on the genes symbols displayed in red in the genomic region image. Further details about the SNP from the HapMap project can be found by clicking on the pie chart that shows the allele frequencies observed in the different HapMap population samples.

The second part of this page displays information about the effect of the SNP on the phenotype with which it is associated and the analysis method that was used to uncover the association. A detailed description of the different analysis methods used can be found in the association analysis section of this website. The phenotype x genotype graph plots the mean phenotype (y-axis) as a function of age range (x-axis) and genotype (different lines) broken down by sex (top and bottom panels). The top panels shows values for male study participants. The bottom panels show values for female study participants. The left-hand panels show the mean phenotype value (including error bars indicating the standard error of the mean) while the right hand panels show the number of study participants in each age range as a function of genotype and sex. Phenotypic means are plotted for all age x genotype x gender categories that include more than twenty participants.

Genome Browser. The genome browser can be searched by chromosomal coordinates or cytoband, HUGO gene name, refseq transcript ID, or dbSNP ID. Detailed help on using the Genome Browser can be found in the GBrowse help pages.

Gene & Protein Details. To facilitate further exploration of the possible biological implications of the associations, we provide detailed gene information which is reached by hyperlinks from the representations of the EntrezGene Loci in the images generated by the GMOD Genome Browser. These pages provide information about gene names, HUGO symbols, synonyms, protein products, a short description of the gene's function, gene ontology information, protein complexes that contain protein products of the locus, and a sampling of manuscripts related to the gene or its products. This information is collected from public sources such as EntrezGene [Maglott et al., 2005] and RefSeq [Wheeler et al., 2005] as well as the BIND Database [Alafarano et al., 2005] and pulled into GMED on demand from the Cognia Molecular Web Service provided by Cognia, Inc. Literature abstracts and links to full-text articles are pulled into GMED on demand from NCBI's PubMed.

references

Alfarano C, Andrade CE, Anthony K, Bahroos N, Bajec M, Bantoft K, Betel D, Bobechko B, Boutilier K, Burgess E et al: The Biomolecular Interaction Network Database and related tools 2005 update. Nucleic Acids Res 2005, 33(Database issue):D418-424.

Maglott D, Ostell J, Pruitt KD, Tatusova T: Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res 2005, 33(Database issue):D54-58.

Perusse, L., Rankinen, T., Zuberi, A., Chagnon, Y. C., Weisnagel, S. J., Argyropoulos, G., Walts, B., Snyder, E. E., and Bouchard, C. (2005). The human obesity gene map: the 2004 update. Obes Res 13, 381-490.

Wheeler DL, Barrett T, Benson DA, Bryant SH, Canese K, Church DM, DiCuccio M, Edgar R, Federhen S, Helmberg W et al: Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 2005, 33(Database issue):D39-45.

Karolchik D, Baertsch R, Diekhans M, Furey TS, Hinrichs A, Lu YT, Roskin KM, Schwartz M, Sugnet CW, Thomas DJ et al: The UCSC Genome Browser Database. 2003, 31(1):51-54.

Hirschhorn, J. N., Lohmueller, K., Byrne, E., and Hirschhorn, K. (2002). A comprehensive review of genetic association studies. Genet Med 4, 45-61.

Stein LD, Mungall C, Shu S, Caudy M, Mangone M, Day A, Nickerson E, Stajich JE, Harris TW, Arva A et al: The generic genome browser: a building block for a model organism system database. Genome Res 2002, 12(10):1599-1610.