• Dominique J Verlaan, Soizik Berlivet, Gary M Hunninghake, Anne-Marie Madore, Mathieu Larivière, Sanny Moussette, Elin Grundberg, Tony Kwan, Manon Ouimet, Bing Ge, Rose Hoberman, Marcin Swiatek, Joana Dias, Kevin C L Lam, Vonda Koka, Eef Harmsen, Manuel Soto-Quiros, Lydiana Avila, Juan C Celedón, Scott T Weiss, Ken Dewar, Daniel Sinnett, Catherine Laprise, Benjamin A Raby, Tomi Pastinen, and Anna K Naumova.
• McGill University and Genome Quebec Innovation Centre, Quebec, Canada.
• Am. J. Hum. Genet. 2009 Sep 1; 85 (3): 377-93.

AbstractCommon 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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