期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 23, 页码 9607-9612出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1219099110
关键词
systems biology; regulatory genomics; translational bioinformatics
资金
- National Science Foundation Graduate Research Fellowship Program
- National Institutes of Health (NIH) [LM007033]
- Hewlett Packard Foundation
- Lucile Packard Foundation for Children's Health
- National Defense Science and Engineering Graduate Fellowship
- NIH
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 NF kappa B, we find that disease-associated SNPs are enriched in NF kappa B binding regions overall, and specifically for inflammatory-mediated diseases, such as asthma, rheumatoid arthritis, and coronary artery disease. Using genomewide variation in transcription factor-binding data, we find that NF kappa B 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.
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