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

作者信息

Raychaudhuri Soumya, Plenge Robert M, Rossin Elizabeth J, Ng Aylwin C Y, Purcell Shaun M, Sklar Pamela, Scolnick Edward M, Xavier Ramnik J, Altshuler David, Daly Mark J

机构信息

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.

出版信息

PLoS Genet. 2009 Jun;5(6):e1000534. doi: 10.1371/journal.pgen.1000534. Epub 2009 Jun 26.


DOI:10.1371/journal.pgen.1000534
PMID:19557189
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2694358/
Abstract

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/).

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97c8/2694358/b8808bbf2b8f/pgen.1000534.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97c8/2694358/60fd4261d4bb/pgen.1000534.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97c8/2694358/9e24a7175807/pgen.1000534.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97c8/2694358/b52f625fe6d2/pgen.1000534.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97c8/2694358/b8808bbf2b8f/pgen.1000534.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97c8/2694358/60fd4261d4bb/pgen.1000534.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97c8/2694358/9e24a7175807/pgen.1000534.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97c8/2694358/b52f625fe6d2/pgen.1000534.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/97c8/2694358/b8808bbf2b8f/pgen.1000534.g004.jpg

相似文献

[1]
Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions.

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[2]
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[3]
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[10]
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本文引用的文献

[1]
FitSNPs: highly differentially expressed genes are more likely to have variants associated with disease.

Genome Biol. 2008

[2]
Large recurrent microdeletions associated with schizophrenia.

Nature. 2008-9-11

[3]
Rare chromosomal deletions and duplications increase risk of schizophrenia.

Nature. 2008-9-11

[4]
Seeking a new biology through text mining.

Cell. 2008-7-11

[5]
Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.

Nat Genet. 2008-8

[6]
Strong association of de novo copy number mutations with sporadic schizophrenia.

Nat Genet. 2008-7

[7]
Genetic-linkage mapping of complex hereditary disorders to a whole-genome molecular-interaction network.

Genome Res. 2008-7

[8]
Genome-wide association analysis identifies 20 loci that influence adult height.

Nat Genet. 2008-5

[9]
Many sequence variants affecting diversity of adult human height.

Nat Genet. 2008-5

[10]
Identification of ten loci associated with height highlights new biological pathways in human growth.

Nat Genet. 2008-5

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