Journal article
Identification of functional non-coding variants associated with orofacial cleft
Nature communications, Vol.16(1), 6545
07/16/2025
DOI: 10.1038/s41467-025-61734-w
PMCID: PMC12267437
PMID: 40670354
Abstract
Oral facial cleft (OFC) comprises cleft lip with or without cleft palate (CL/P) or cleft palate only. Genome wide association studies (GWAS) of isolated OFC have identified common single nucleotide polymorphisms (SNPs) in many genomic loci where the presumed effector gene (for example, IRF6 in the 1q32 locus) is expressed in embryonic oral epithelium. To identify candidates for functional SNPs at eight such loci we conduct a massively parallel reporter assay in a fetal oral epithelial cell line, revealing SNPs with allele-specific effects on enhancer activity. We filter these SNPs against chromatin-mark evidence of enhancers and test a subset in traditional reporter assays, which support the candidacy of SNPs at loci containing FOXE1, IRF6, MAFB, TFAP2A, and TP63. For two SNPs near IRF6 and one near FOXE1, we engineer the genome of induced pluripotent stem cells, differentiate the cells into embryonic oral epithelium, and discover allele-specific effects on the levels of effector gene expression, and, in two cases, the binding affinity of transcription factors FOXE1 or ETS2. Conditional analyses of GWAS data suggest the two functional SNPs near IRF6 account for the majority of risk for CL/P at this locus. This study connects genetic variation associated with OFC to mechanisms of pathogenesis.
Details
- Title: Subtitle
- Identification of functional non-coding variants associated with orofacial cleft
- Creators
- Priyanka Kumari - University of WashingtonRyan Z Friedman - Washington University in St. LouisSarah W Curtis - Emory UniversityLira Pi - Cencora-PharmaLex, Conshohocken, PA, USAKitt Paraiso - Lawrence Berkeley National LaboratoryAxel Visel - Lawrence Berkeley National LaboratoryLindsey Rhea - University of IowaMartine Dunnwald - University of IowaAnjali P Patni - University of WashingtonDaniel Mar - University of WashingtonKarol Bomsztyk - University of WashingtonJulie Mathieu - University of WashingtonHannele Ruohola-Baker - World Institute on DisabilityElizabeth J Leslie-Clarkson - Emory University School of MedicineMichael A White - Washington University in St. LouisBarak A Cohen - Washington University in St. LouisRobert A Cornell - University of Washington
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.16(1), 6545
- DOI
- 10.1038/s41467-025-61734-w
- PMID
- 40670354
- PMCID
- PMC12267437
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- NATURE PORTFOLIO
- Grant note
- DE027362 / U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR)
- Language
- English
- Date published
- 07/16/2025
- Academic Unit
- Anatomy and Cell Biology; Craniofacial Anomalies Research Center
- Record Identifier
- 9984848120702771
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