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Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions.

PLoS genetics | 2009

Translating a set of disease regions into insight about pathogenic mechanisms requires not only the ability to identify the key disease genes within them, but also the biological relationships among those key genes. Here we describe a statistical method, Gene Relationships Among Implicated Loci (GRAIL), that takes a list of disease regions and automatically assesses the degree of relatedness of implicated genes using 250,000 PubMed abstracts. We first evaluated GRAIL by assessing its ability to identify subsets of highly related genes in common pathways from validated lipid and height SNP associations from recent genome-wide studies. We then tested GRAIL, by assessing its ability to separate true disease regions from many false positive disease regions in two separate practical applications in human genetics. First, we took 74 nominally associated Crohn's disease SNPs and applied GRAIL to identify a subset of 13 SNPs with highly related genes. Of these, ten convincingly validated in follow-up genotyping; genotyping results for the remaining three were inconclusive. Next, we applied GRAIL to 165 rare deletion events seen in schizophrenia cases (less than one-third of which are contributing to disease risk). We demonstrate that GRAIL is able to identify a subset of 16 deletions containing highly related genes; many of these genes are expressed in the central nervous system and play a role in neuronal synapses. GRAIL offers a statistically robust approach to identifying functionally related genes from across multiple disease regions--that likely represent key disease pathways. An online version of this method is available for public use (http://www.broad.mit.edu/mpg/grail/).

Pubmed ID: 19557189 RIS Download

Research resources used in this publication

None found

Antibodies used in this publication

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Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK040561
  • Agency: NHGRI NIH HHS, United States
    Id: U01 HG004171
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007753
  • Agency: NIAMS NIH HHS, United States
    Id: T32 AR007530
  • Agency: NHGRI NIH HHS, United States
    Id: U01HG004171
  • Agency: NIAMS NIH HHS, United States
    Id: T32AR007530-23
  • Agency: NIAMS NIH HHS, United States
    Id: K08 AR055688
  • Agency: NIAMS NIH HHS, United States
    Id: K08 AR055688-01A1
  • Agency: NIAMS NIH HHS, United States
    Id: 1K08AR055688-01A1
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK040561-14
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK083759

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This is a list of tools and resources that we have found mentioned in this publication.


Gene Relationships Across Implicated Loci (tool)

RRID:SCR_008537

A tool to examine relationships between genes in different disease associated loci. Given several genomic regions or SNPs associated with a particular phenotype or disease, GRAIL looks for similarities in the published scientific text among the associated genes. As input, users can upload either (1) SNPs that have emerged from a genome-wide association study or (2) genomic regions that have emerged from a linkage scan or are associated common or rare copy number variants. SNPs should be listed according to their rs#''s and must be listed in HapMap. Genomic Regions are specified by a user-defined identifier, the chromosome that it is located on, and the start and end base-pair positions for the region. Grail can take two sets of inputs - Query regions and Seed regions. Seed regions are definitely associated SNPs or genomic regions, and Query regions are those regions that the user is attempting to evaluate agains them. In many applications the two sets are identical. Based on textual relationships between genes, GRAIL assigns a p-value to each region suggesting its degree of functional connectivity, and picks the best candidate gene. GRAIL is developed by Soumya Raychaudhuri in the labs of David Altshuler and Mark Daly at the Center for Human Genetic Research of Massachusetts General Hospital and Harvard Medical School, and the Broad Institute. GRAIL is described in manuscript, currently in preparation.

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Entrez Gene (tool)

RRID:SCR_002473

Database for genomes that have been completely sequenced, have active research community to contribute gene-specific information, or that are scheduled for intense sequence analysis. Includes nomenclature, map location, gene products and their attributes, markers, phenotypes, and links to citations, sequences, variation details, maps, expression, homologs, protein domains and external databases. All entries follow NCBI's format for data collections. Content of Entrez Gene represents result of curation and automated integration of data from NCBI's Reference Sequence project (RefSeq), from collaborating model organism databases, and from many other databases available from NCBI. Records are assigned unique, stable and tracked integers as identifiers. Content is updated as new information becomes available.

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