Linking disease associations with regulatory information in the human genome
MetadataShow full item record
AbstractGenome-wide association studies have been successful in identifying single nucleotide polymorphisms (SNPs) associated with a large number of phenotypes. However, an associated SNP is likely part of a larger region of linkage disequilibrium. This makes it difficult to precisely identify the SNPs that have a biological link with the phenotype. We have systematically investigated the association of multiple types of ENCODE data with disease-associated SNPs and show that there is significant enrichment for functional SNPs among the currently identified associations. This enrichment is strongest when integrating multiple sources of functional information and when highest confidence disease-associated SNPs are used. We propose an approach that integrates multiple types of functional data generated by the ENCODE Consortium to help identify "functional SNPs" that may be associated with the disease phenotype. Our approach generates putative functional annotations for up to 80% of all previously reported associations. We show that for most associations, the functional SNP most strongly supported by experimental evidence is a SNP in linkage disequilibrium with the reported association rather than the reported SNP itself. Our results show that the experimental data sets generated by the ENCODE Consortium can be successfully used to suggest functional hypotheses for variants associated with diseases and other phenotypes.
CitationSchaub MA, Boyle AP, Kundaje A, Batzoglou S, Snyder M (2012) Linking disease associations with regulatory information in the human genome. Genome Research 22: 1748–1759. Available: http://dx.doi.org/10.1101/gr.136127.111.
SponsorsWe thank Ross Hardison, Ewan Birney, Jason Ernst, KonradKarczewski, Manoj Hariharan, and the members of the Batzogloulaboratory for suggestions and comments. We thank the anonymousreviewers for valuable feedback and suggestions. We thankthe ENCODE Consortium, the Office of Population Genomics atthe National Human Genome Research Institute, the HapMapConsortium, and the Genome Bioinformatics Group at the Universityof California–Santa Cruz for generating the data and toolsused in this work. This work was supported in part by the ENCODEConsortium under Grant No. NIH 5U54 HG 004558, by theNational Science Foundation under Grant No. 0640211, fundingfrom the Beta Cell Consortium, and by a King Abdullah Universityof Science and Technology research grant. M.A.S. was supportedin part by a Richard and Naomi Horowitz Stanford GraduateFellowship. A.K. was partially supported by an ENCODE analysissubcontract.
PublisherCold Spring Harbor Laboratory Press
PubMed Central IDPMC3431491
CollectionsPublications Acknowledging KAUST Support
- On the identification of potential regulatory variants within genome wide association candidate SNP sets.
- Authors: Chen CY, Chang IS, Hsiung CA, Wasserman WW
- Issue date: 2014 Jun 11
- FunciSNP: an R/bioconductor tool integrating functional non-coding data sets with genetic association studies to identify candidate regulatory SNPs.
- Authors: Coetzee SG, Rhie SK, Berman BP, Coetzee GA, Noushmehr H
- Issue date: 2012 Oct
- HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants.
- Authors: Ward LD, Kellis M
- Issue date: 2012 Jan
- Strategies to fine-map genetic associations with lipid levels by combining epigenomic annotations and liver-specific transcription profiles.
- Authors: Lo KS, Vadlamudi S, Fogarty MP, Mohlke KL, Lettre G
- Issue date: 2014 Aug
- Data integration for functional annotation of regulatory single nucleotide polymorphisms associated with Alzheimer's disease susceptibility.
- Authors: Amber S, Zahid S
- Issue date: 2018 Sep 25