title: is-rSNP: a novel technique for in silico regulatory SNP detection.
abstract: BACKGROUND
  Determining the functional impact of non-coding disease-associated single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) is challenging. Many of these SNPs are likely to be regulatory SNPs (rSNPs): variations which affect the ability of a transcription factor (TF) to bind to DNA. However, experimental procedures for identifying rSNPs are expensive and labour intensive. Therefore, in silico methods are required for rSNP prediction. By scoring two alleles with a TF position weight matrix (PWM), it can be determined which SNPs are likely rSNPs. However, predictions in this manner are noisy and no method exists that determines the statistical significance of a nucleotide variation on a PWM score.
  
  
  RESULTS
  We have designed an algorithm for in silico rSNP detection called is-rSNP. We employ novel convolution methods to determine the complete distributions of PWM scores and ratios between allele scores, facilitating assignment of statistical significance to rSNP effects. We have tested our method on 41 experimentally verified rSNPs, correctly predicting the disrupted TF in 28 cases. We also analysed 146 disease-associated SNPs with no known functional impact in an attempt to identify candidate rSNPs. Of the 11 significantly predicted disrupted TFs, 9 had previous evidence of being associated with the disease in the literature. These results demonstrate that is-rSNP is suitable for high-throughput screening of SNPs for potential regulatory function. This is a useful and important tool in the interpretation of GWAS.
  
  
  BACKGROUND
  is-rSNP software is available for use at: www.genomics.csse.unimelb.edu.au/is-rSNP.
authors.affiliation: Department of Computer Science and Software Engineering, University of Melbourne, Victoria, Australia. gmaci@csse.unimelb.edu.au
authors.forename: Geoff
authors.initials: G
authors.lastname: Macintyre
authors.forename: James
authors.initials: J
authors.lastname: Bailey
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.forename: Adam
authors.initials: A
authors.lastname: Kowalczyk
mesh_terms: D000465:Algorithms; D000483:Alleles; D004247:DNA / Q000032:analysis; D030541:Databases, Genetic; D004194:Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D056510:Position-Specific Scoring Matrices; D012045:Regulatory Sequences, Nucleic Acid; D012984:Software; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D004247:DNA
references.citation: Nat Methods. 2009 Apr;6(4):283-9
references.pmid: 19305407
references.citation: Curr HIV Res. 2008 Jun;6(4):286-95
references.pmid: 18691027
references.citation: Nat Clin Pract Gastroenterol Hepatol. 2006 Jul;3(7):390-407
references.pmid: 16819502
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D108-10
references.pmid: 16381825
references.citation: Hum Mol Genet. 2010 Mar 1;19(5):803-14
references.pmid: 20007505
references.citation: Hum Mutat. 2010 Apr;31(4):477-83
references.pmid: 20127973
references.citation: Mol Psychiatry. 2003 Nov;8(11):901-10
references.pmid: 14593427
references.citation: Clin Exp Pharmacol Physiol. 2006 Apr;33(4):395-9
references.pmid: 16620308
references.citation: Algorithms Mol Biol. 2007 Dec 11;2:15
references.pmid: 18072973
references.citation: J Neural Transm (Vienna). 2002 Sep;109(9):1181-8
references.pmid: 12203044
references.citation: Bioinformatics. 2006 Mar 1;22(5):637-40
references.pmid: 16397004
references.citation: J Neurochem. 2001 Apr;77(1):239-52
references.pmid: 11279280
references.citation: Nature. 2009 Nov 5;462(7269):58-64
references.pmid: 19890323
references.citation: J Clin Oncol. 2009 Feb 1;27(4):619-28
references.pmid: 19075268
references.citation: Nature. 2009 Feb 12;457(7231):854-8
references.pmid: 19212405
references.citation: Mech Dev. 2009 Mar-Apr;126(3-4):220-9
references.pmid: 19027849
references.citation: PLoS One. 2009;4(5):e5501
references.pmid: 19434238
references.citation: Hum Mol Genet. 2003 Feb 15;12(4):423-33
references.pmid: 12566389
references.citation: J Neuroimmunol. 2006 Jul;176(1-2):174-80
references.pmid: 16750572
references.citation: Nucleic Acids Res. 2001 Jan 1;29(1):312-6
references.pmid: 11125123
references.citation: PLoS Comput Biol. 2008 Jan;4(1):e5
references.pmid: 18208319
references.citation: Comput Appl Biosci. 1996 Oct;12(5):431-9
references.pmid: 8996792
references.citation: Nat Genet. 2008 Nov;40(11):1341-7
references.pmid: 18836445
references.citation: Genome Res. 2004 Jun;14(6):1188-90
references.pmid: 15173120
references.citation: PLoS Comput Biol. 2009 Nov;5(11):e1000566
references.pmid: 19918365
references.citation: Genes Immun. 2004 Jun;5(4):274-82
references.pmid: 15085176