Faculty, Staff and Student Publications
Publication Date
11-6-2024
Journal
Nature Communications
Abstract
In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10-34, OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P = 7.2 × 10-5), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland (P = 8.82 × 10-28) and Estonia (P = 1.25 × 10-5). The risk allele of rs570516915 alters a conserved binding site for the transcription factor IRF6 within an enhancer (MCS-9.7) upstream of the IRF6 gene and diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level of IRF6, suggesting impaired IRF6 autoregulation as a molecular mechanism underlying the risk for CP.
Keywords
Humans, Finland, Interferon Regulatory Factors, Cleft Palate, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Predisposition to Disease, Incidence, Gene Frequency, Cleft Lip, Female, Male, Estonia, Alleles, Genome-wide association studies, CRISPR-Cas9 genome editing
DOI
10.1038/s41467-024-53634-2
PMID
39500877
PMCID
PMC11538390
PubMedCentral® Posted Date
11-6-2024
PubMedCentral® Full Text Version
Post-print
Recommended Citation
Rahimov, Fedik; Nieminen, Pekka; Kumari, Priyanka; Juuri, Emma; Nikopensius, Tiit; Paraiso, Kitt; German, Jakob; Karvanen, Antti; Kals, Mart; Elnahas, Abdelrahman G; Karjalainen, Juha; Kurki, Mitja; Palotie, Aarno; Estonian Biobank Research Team; FinnGen; Heliövaara, Arja; Esko, Tõnu; Jukarainen, Sakari; Palta, Priit; Ganna, Andrea; Patni, Anjali P; Mar, Daniel; Bomsztyk, Karol; Mathieu, Julie; Ruohola-Baker, Hannele; Visel, Axel; Fakhouri, Walid D; Schutte, Brian C; Cornell, Robert A; and Rice, David P, "High Incidence and Geographic Distribution of Cleft Palate in Finland Are Associated With the IRF6 Gene" (2024). Faculty, Staff and Student Publications. 60.
https://digitalcommons.library.tmc.edu/uthdb_docs/60
Published Open-Access
yes
