期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 85, 期 3, 页码 377-393出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2009.08.007
关键词
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资金
- Genome Quebec
- Genome Canada
- Canadian Institutes of Health Research (CIHR)
- National Heart, Lung and Blood Institute, National Institutes of Health [U01 HL075419, U01 HL65899, P01 HL083069, R01 HL 086601, T32 HL07427, HL04370, HL66289]
- NHGRI
- Burroughs Wellcome Fund
- Massachusetts General Hospital
- Broad Institute
Common SNPs in the chromosome 17q12-q21 region alter the risk for asthma, type I diabetes, primary biliary cirrhosis, and Crohn disease. Previous reports by us and others have linked the disease-associated genetic variants with changes in expression of GSDMB and ORMDL3 transcripts in human lymphoblastoid cell lines (LCLs). The variants also alter regulation of other transcripts, and this domain-wide cis-regulatory effect suggests a mechanism involving long-range chromatin interactions. Here, we further dissect the disease-linked haplotype and identify putative causal DNA variants via a combination of genetic and functional analyses. First, high-throughput resequencing of the region and genotyping of potential candidate variants were performed. Next, additional mapping of allelic expression differences in Yoruba HapMap LCLs allowed us to fine-map the basis of the cis-regulatory differences to a handful of candidate functional variants. Functional assays identified allele-specific differences in nucleosome distribution, an allele-specific association with the insulator protein CTCF, as well as a weak promoter activity for rs12936231. Overall, this study shows a common disease allele linked to changes in CTCF binding and nucleosome occupancy leading to altered domain-wide cis-regulation. Finally, a strong association between asthma and cis-regulatory haplotypes was observed in three independent family-based cohorts (p = 1.78 x 10(-8)). This study demonstrates the requirement of multiple parallel allele-specific tools for the investigation of noncoding disease variants and functional fine-mapping of human disease-associated haplotypes.
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