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Genome Biology

, 9:R170

First Online: 05 December 2008Received: 17 June 2008Revised: 26 September 2008Accepted: 05 December 2008

Abstract

BackgroundCandidate single nucleotide polymorphisms SNPs from genome-wide association studies GWASs were often selected for validation based on their functional annotation, which was inadequate and biased. We propose to use the more than 200,000 microarray studies in the Gene Expression Omnibus to systematically prioritize candidate SNPs from GWASs.

ResultsWe analyzed all human microarray studies from the Gene Expression Omnibus, and calculated the observed frequency of differential expression, which we called differential expression ratio, for every human gene. Analysis conducted in a comprehensive list of curated disease genes revealed a positive association between differential expression ratio values and the likelihood of harboring disease-associated variants. By considering highly differentially expressed genes, we were able to rediscover disease genes with 79% specificity and 37% sensitivity. We successfully distinguished true disease genes from false positives in multiple GWASs for multiple diseases. We then derived a list of functionally interpolating SNPs fitSNPs to analyze the top seven loci of Wellcome Trust Case Control Consortium type 1 diabetes mellitus GWASs, rediscovered all type 1 diabetes mellitus genes, and predicted a novel gene KIAA1109 for an unexplained locus 4q27. We suggest that fitSNPs would work equally well for both Mendelian and complex diseases being more effective for cancer and proposed candidate genes to sequence for their association with 597 syndromes with unknown molecular basis.

ConclusionsOur study demonstrates that highly differentially expressed genes are more likely to harbor disease-associated DNA variants. FitSNPs can serve as an effective tool to systematically prioritize candidate SNPs from GWASs.

AbbreviationsCNVcopy number variation

DERdifferential expression ratio

fitSNPsfunctionally interpolating single nucleotide polymorphisms

GADGenetic Association Database

GEOGene Expression Omnibus

GWASgenome-wide association study

HGMDHuman Gene Mutation Database

OMIMOnline Mendelian Inheritance in Man

SAMsignificance analysis of microarrays

SLEsystemic lupus erythemetosus

SNPsingle nucleotide polymorphism

T1DMtype 1 diabetes mellitus

T2DMtype 2 diabetes mellitus

UCSCUniversity of California Santa Cruz

WTCCCWellcome Trust Case Control Consortium.

Electronic supplementary materialThe online version of this article doi:10.1186-gb-2008-9-12-r170 contains supplementary material, which is available to authorized users.

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Autor: Rong Chen - Alex A Morgan - Joel Dudley - Tarangini Deshpande - Li Li - Keiichi Kodama - Annie P Chiang - Atul J Butte

Fuente: https://link.springer.com/



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