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

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; 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.; Rice, David P.

doi:10.1038/s41467-024-53634-2

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

Journal Article · 06 November 2024 · Nature Communications

DOI: https://doi.org/10.1038/s41467-024-53634-2 · OSTI ID:2481710

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^[2]; Nikopensius, Tiit ^[4]; Paraiso, Kitt ^[5];

^[6]; Karvanen, Antti ^[2];

^[2]; Elnahas, Abdelrahman G. ^[4]; Karjalainen, Juha ^[7]; Kurki, Mitja ^[7];

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^[2]; Esko, Tõnu ^[4];

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^[8]; Mar, Daniel ^[9] more »

AbbVie Inc, North Chicago, IL (United States)
University of Helsinki (Finland)
University of Iowa, Iowa City, IA (United States); University of Washington, Seattle, WA (United States)
University of Tartu (Estonia)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
University of Helsinki (Finland); Broad Institute of Harvard and MIT, Cambridge, MA (United States)
University of Helsinki (Finland); Broad Institute of Harvard and MIT, Cambridge, MA (United States); Massachusetts General Hospital, Boston, MA (United States)
University of Washington, Seattle, WA (United States); University of Washington School of Medicine, Seattle, WA (United States); SRM Institute of Science and Technology, Chennai (India)
University of Washington School of Medicine, Seattle, WA (United States); University of Washington, Seattle, WA (United States)
University of Washington School of Medicine, Seattle, WA (United States); University of Washington, Seattle, WA (United States); Matchstick Technologies, Inc, Kirkland, WA (United States)
University of Washington School of Medicine, Seattle, WA (United States)
University of Washington School of Medicine, Seattle, WA (United States); Brotman Baty Institute for Precision Medicine, Seattle, WA (United States); University of Washington, Seattle, WA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); University of California, Merced, CA (United States)
University of Texas Health Science Center at Houston, Houston, TX (United States)
Michigan State University, East Lansing, MI (United States)
University of Iowa, Iowa City, IA (United States); University of Washington, Seattle, WA (United States); University of Washington School of Medicine, Seattle, WA (United States)

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: Business Finland; Center of Excellence for Genomics and Translational Medicine; Estonian Research Council; European Research Council (ERC); European Union; Finnish Dental Society Apollonia; HUS Helsinki University Hospital Research Foundation; NIDCR; NIGMS; U.S. National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science (BSS)

Contributing Organization:: Estonian Biobank Research Team; FinnGen

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2481710

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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

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