Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease.
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.
Verlaan
Dominique J
DJ
McGill University and Genome Quebec Innovation Centre, Quebec, Canada.
Berlivet
Soizik
S
Hunninghake
Gary M
GM
Madore
Anne-Marie
AM
Larivière
Mathieu
M
Moussette
Sanny
S
Grundberg
Elin
E
Kwan
Tony
T
Ouimet
Manon
M
Ge
Bing
B
Hoberman
Rose
R
Swiatek
Marcin
M
Dias
Joana
J
Lam
Kevin C L
KC
Koka
Vonda
V
Harmsen
Eef
E
Soto-Quiros
Manuel
M
Avila
Lydiana
L
Celedón
Juan C
JC
Weiss
Scott T
ST
Dewar
Ken
K
Sinnett
Daniel
D
Laprise
Catherine
C
Raby
Benjamin A
BA
Pastinen
Tomi
T
Naumova
Anna K
AK
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
D004527:Egg Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C527978:GSDMB protein, human; D000094524:Gasdermins; C464399:ORMDL3 protein, human; C479482:ZPBP2 protein, human