title: Systematic functional regulatory assessment of disease-associated variants.
abstract: Genome-wide association studies have discovered many genetic loci associated with disease traits, but the functional molecular basis of these associations is often unresolved. Genome-wide regulatory and gene expression profiles measured across individuals and diseases reflect downstream effects of genetic variation and may allow for functional assessment of disease-associated loci. Here, we present a unique approach for systematic integration of genetic disease associations, transcription factor binding among individuals, and gene expression data to assess the functional consequences of variants associated with hundreds of human diseases. In an analysis of genome-wide binding profiles of NFκB, we find that disease-associated SNPs are enriched in NFκB binding regions overall, and specifically for inflammatory-mediated diseases, such as asthma, rheumatoid arthritis, and coronary artery disease. Using genome-wide variation in transcription factor-binding data, we find that NFκB binding is often correlated with disease-associated variants in a genotype-specific and allele-specific manner. Furthermore, we show that this binding variation is often related to expression of nearby genes, which are also found to have altered expression in independent profiling of the variant-associated disease condition. Thus, using this integrative approach, we provide a unique means to assign putative function to many disease-associated SNPs.
authors.affiliation: Biomedical Informatics Training Program, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karczewski
authors.forename: Joel T
authors.initials: JT
authors.lastname: Dudley
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kukurba
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
mesh_terms: D019295:Computational Biology / Q000379:methods*; D020869:Gene Expression Profiling; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D049490:Systems Biology / Q000379:methods*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D014157:Transcription Factors
keywords: regulatory genomics; systems biology; translational bioinformatics