title: Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease.
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.
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Quebec, Canada.
authors.forename: Dominique J
authors.initials: DJ
authors.lastname: Verlaan
authors.forename: Soizik
authors.initials: S
authors.lastname: Berlivet
authors.forename: Gary M
authors.initials: GM
authors.lastname: Hunninghake
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Madore
authors.forename: Mathieu
authors.initials: M
authors.lastname: Larivière
authors.forename: Sanny
authors.initials: S
authors.lastname: Moussette
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.forename: Manon
authors.initials: M
authors.lastname: Ouimet
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.forename: Rose
authors.initials: R
authors.lastname: Hoberman
authors.forename: Marcin
authors.initials: M
authors.lastname: Swiatek
authors.forename: Joana
authors.initials: J
authors.lastname: Dias
authors.forename: Kevin C L
authors.initials: KC
authors.lastname: Lam
authors.forename: Vonda
authors.initials: V
authors.lastname: Koka
authors.forename: Eef
authors.initials: E
authors.lastname: Harmsen
authors.forename: Manuel
authors.initials: M
authors.lastname: Soto-Quiros
authors.forename: Lydiana
authors.initials: L
authors.lastname: Avila
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Ken
authors.initials: K
authors.lastname: Dewar
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.forename: Anna K
authors.initials: AK
authors.lastname: Naumova
mesh_terms: D000293:Adolescent; D000483:Alleles; D001249:Asthma / Q000150:complications / Q000235:genetics*; D001327:Autoimmune Diseases / Q000150:complications / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004252:DNA Mutational Analysis; D004527:Egg Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D044465:White People / Q000235:genetics; D000094524:Gasdermins
chemical_list: D004527:Egg Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C527978:GSDMB protein, human; D000094524:Gasdermins; C464399:ORMDL3 protein, human; C479482:ZPBP2 protein, human