High incidence and geographic distribution of cleft palate in Finland are associated with the IRF6 gene

Fedik Rahimov, Pekka Nieminen, Priyanka Kumari, Emma Juuri, Tiit Nikopensius, Kitt Paraiso, Jakob German, Antti Karvanen, Mart Kals, Abdelrahman G. Elnahas, Juha Karjalainen, Mitja Kurki, Aarno Palotie, Arja Heliövaara, Tõnu Esko, Sakari Jukarainen, Priit Palta, Andrea Ganna, Anjali P. Patni, Daniel Mar, Karol Bomsztyk, Julie Mathieu, Hannele Ruohola-Baker, Axel Visel, Walid D. Fakhouri, Brian C. Schutte (), Robert A. Cornell () and David P. Rice ()
Additional contact information
Fedik Rahimov: AbbVie Inc
Pekka Nieminen: University of Helsinki
Priyanka Kumari: University of Iowa
Emma Juuri: University of Helsinki and Helsinki University Hospital
Tiit Nikopensius: University of Tartu
Kitt Paraiso: Lawrence Berkeley Laboratories
Jakob German: University of Helsinki
Antti Karvanen: University of Helsinki
Mart Kals: University of Tartu
Abdelrahman G. Elnahas: University of Tartu
Juha Karjalainen: University of Helsinki
Mitja Kurki: University of Helsinki
Aarno Palotie: University of Helsinki
Arja Heliövaara: University of Helsinki and Helsinki University Hospital
Tõnu Esko: University of Tartu
Sakari Jukarainen: University of Helsinki
Priit Palta: University of Tartu
Andrea Ganna: University of Helsinki
Anjali P. Patni: University of Washington
Daniel Mar: University of Washington School of Medicine
Karol Bomsztyk: University of Washington School of Medicine
Julie Mathieu: University of Washington School of Medicine
Hannele Ruohola-Baker: University of Washington
Axel Visel: Lawrence Berkeley Laboratories
Walid D. Fakhouri: University of Texas Health Science Center at Houston
Brian C. Schutte: Michigan State University
Robert A. Cornell: University of Iowa
David P. Rice: University of Helsinki and Helsinki University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53634-2

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