Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated with the Risk of Asthma and Autoimmune Disease Export

@article{verlaan2009chromatin, 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.}, author = {Verlaan, Dominique J. and Berlivet, Soizik and Hunninghake, Gary M. and Madore, Anne-Marie and Larivi\`{e}re, Mathieu and Moussette, Sanny and Grundberg, Elin and Kwan, Tony and Ouimet, Manon and Ge, Bing}, citeulike-article-id = {5750747}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.ajhg.2009.08.007}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S0002929709003504}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19732864}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19732864}, day = {11}, doi = {10.1016/j.ajhg.2009.08.007}, issn = {00029297}, journal = {The American Journal of Human Genetics}, keywords = {association, chromatin, cis-regulation, expression\_domain, nucleosomes}, month = {September}, number = {3}, pages = {377--393}, posted-at = {2009-09-08 22:03:52}, priority = {2}, title = {Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated with the Risk of Asthma and Autoimmune Disease}, url = {http://dx.doi.org/10.1016/j.ajhg.2009.08.007}, volume = {85}, year = {2009} }

TY - JOUR ID - verlaan2009chromatin L3 - citeulike-article-id:5750747 N2 - 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. IS - 3 JF - The American Journal of Human Genetics SN - 00029297 EP - 393 TI - Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated with the Risk of Asthma and Autoimmune Disease VL - 85 SP - 377 KW - association KW - chromatin KW - cis-regulation KW - expression_domain KW - nucleosomes AU - Verlaan, Dominique AU - Berlivet, Soizik AU - Hunninghake, Gary AU - Madore, Anne-Marie AU - Larivière, Mathieu AU - Moussette, Sanny AU - Grundberg, Elin AU - Kwan, Tony AU - Ouimet, Manon AU - Ge, Bing PY - 2009/09/11/ UR - http://dx.doi.org/10.1016/j.ajhg.2009.08.007 ER -