High incidence and geographic distribution of cleft palate cases in Finland are associated with a regulatory variant in IRF6
Rahimov, F.; Nieminen, P.; Kumari, P.; Juuri, E.; Nikopensius, T.; Paraiso, K.; German, J.; Karvanen, A.; Kals, M.; Elnahas, A. G.; Karjalainen, J.; Kurki, M.; Palotie, A.; FinnGen, ; Estonian Biobank Research Team, ; Heliovaara, A.; Esko, T.; Jukarainen, S.; Palta, P.; Ganna, A.; Patni, A. P.; Mar, D.; Bomsztyk, K.; Mathieu, J.; Ruohola-Baker, H.; Visel, A.; Fakhouri, W. D.; Schutte, B. C.; Cornell, R. A.; Rice, D. P.
Show 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 x 10-34, OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P = 7.2 x 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 x 10-28) and Estonia (P = 1.25 x 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.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Syndrome-informed phenotyping identifies a polygenic background for achondroplasia-like facial variation in the general population 95%
- Exome-wide analysis of congenital kidney anomalies reveals new genes and shared architecture with developmental disorders 94%
- iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity 94%
Similar papers in this journal
- Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy 96%
- Loss-of-function of the Zinc Finger Homeobox 4 ( ZFHX4 ) gene underlies a neurodevelopmental disorder 95%
- The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects 94%
Similar papers in this journal
- Identification and validation of novel candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas 96%
- Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate 95%
- Functional characterization of pathogenic SATB2 missense variants identifies distinct effects on chromatin binding and transcriptional activity 94%
Similar papers in this journal
- Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome 95%
- Copy Number Variants and their Implications for Developmental and Behavioural Problems in Cleft Lip and/or Palate 92%
- Low-Pass Whole Genome Bisulfite Sequencing of Neonatal Dried Blood Spots Identifies a Role for RUNX1 in Down Syndrome DNA Methylation Profiles 92%
Similar papers in this journal
- Association between genes regulating neural pathways for quantitative traits of speech and language disorders 93%
- Discordance between a deep learning model and clinical-grade variant pathogenicity classification in a rare disease cohort 93%
- Whole genome sequencing delineates regulatory and novel genic variants in childhood cardiomyopathy 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.