Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease by Verlaan Dominique J, Berlivet Soizik, Hunninghake Gary M, Madore Anne-Marie, Larivière Mathieu, Moussette Sanny, Grundberg Elin, Kwan Tony, Ouimet Manon, Ge Bing, Hoberman Rose, Swiatek Marcin, Dias Joana, Lam Kevin C L, Koka Vonda, Harmsen Eef, Soto-Quiros Manuel, Avila Lydiana, Celedón Juan C, Weiss Scott T, Dewar Ken, Sinnett Daniel, Laprise Catherine, Raby Benjamin A, Pastinen Tomi, Naumova Anna K in American journal of human genetics (2009). PubMed

Abstract

Common SNPs in the chromosome 17q12-q21 region alter the risk for asthma, type 1 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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