PUBLICATION
Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting
- Authors
- Liu, H., Leslie, E.J., Carlson, J.C., Beaty, T.H., Marazita, M.L., Lidral, A.C., Cornell, R.A.
- ID
- ZDB-PUB-181118-22
- Date
- 2017
- Source
- Nature communications 8: 14759 (Journal)
- Registered Authors
- Cornell, Robert
- Keywords
- none
- MeSH Terms
-
- Alleles
- Animals
- Animals, Genetically Modified
- Biological Assay
- Chromatin/chemistry
- Chromosomes, Human, Pair 1/chemistry*
- Cleft Lip/diagnosis
- Cleft Lip/genetics*
- Cleft Lip/pathology
- Cleft Palate/diagnosis
- Cleft Palate/genetics*
- Cleft Palate/pathology
- Enhancer Elements, Genetic
- GTPase-Activating Proteins/genetics*
- GTPase-Activating Proteins/metabolism
- Gene Expression
- Genes, Reporter
- Genetic Loci
- Genetic Predisposition to Disease*
- Genome-Wide Association Study
- Humans
- Linkage Disequilibrium
- Luciferases/genetics
- Luciferases/metabolism
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Risk Factors
- Transcription Factors/genetics*
- Transcription Factors/metabolism
- Zebrafish
- PubMed
- 28287101 Full text @ Nat. Commun.
Citation
Liu, H., Leslie, E.J., Carlson, J.C., Beaty, T.H., Marazita, M.L., Lidral, A.C., Cornell, R.A. (2017) Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting. Nature communications. 8:14759.
Abstract
Genome-wide association studies (GWAS) do not distinguish between single nucleotide polymorphisms (SNPs) that are causal and those that are merely in linkage-disequilibrium with causal mutations. Here we describe a versatile, functional pipeline and apply it to SNPs at 1p22, a locus identified in several GWAS for non-syndromic cleft lip with or without cleft palate (NS CL/P). First we amplified DNA elements containing the ten most-highly risk-associated SNPs and tested their enhancer activity in vitro, identifying three SNPs with allele-dependent effects on such activity. We then used in vivo reporter assays to test the tissue-specificity of these enhancers, chromatin configuration capture to test enhancer-promoter interactions, and genome editing in vitro to show allele-specific effects on ARHGAP29 expression and cell migration. Our results further indicate that two SNPs affect binding of CL/P-associated transcription factors, and one affects chromatin configuration. These results translate risk into potential mechanisms of pathogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping