{"doi":"10.1101/2024.07.09.24310146","title":"High incidence and geographic distribution of cleft palate cases in Finland are associated with a regulatory variant in <i>IRF6</i>","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 performed a genome-wide association study for orofacial clefts, which include CL/P and CP, in the Finnish population. We identified rs570516915, a single nucleotide polymorphism that is highly enriched in Finns and Estonians, as being 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 disrupts a conserved binding site for the transcription factor IRF6 within a previously characterized enhancer upstream of the IRF6 gene. Through reporter assay experiments we found that the risk allele of rs570516915 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.","journal":"medRxiv","year":2024,"id":491362,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1219769,"name":"Pekka Nieminen","orcid":"0000-0003-2109-124X","position":1,"is_corresponding":false},{"id":457313,"name":"Priyanka Kumari","orcid":"0000-0002-7210-172X","position":2,"is_corresponding":false},{"id":958484,"name":"Emma Juuri","orcid":"0000-0003-3252-9323","position":3,"is_corresponding":false},{"id":1219770,"name":"Tiit Nikopensius","orcid":"0000-0002-0816-7804","position":4,"is_corresponding":false},{"id":398243,"name":"Kitt Paraiso","orcid":"0000-0002-6489-810X","position":5,"is_corresponding":false},{"id":1336963,"name":"Jakob German","orcid":null,"position":6,"is_corresponding":false},{"id":1220288,"name":"Antti Karvanen","orcid":null,"position":7,"is_corresponding":false},{"id":56192,"name":"Mart Kals","orcid":"0000-0003-2090-8780","position":8,"is_corresponding":false},{"id":1202492,"name":"Abdelrahman G. 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