Academic Journal
Trio-based GWAS reveals loci associated with different forms of isolated cleft lip.
| Τίτλος: | Trio-based GWAS reveals loci associated with different forms of isolated cleft lip. |
|---|---|
| Συγγραφείς: | Herrick N; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: noah.herrick@pitt.edu., Erdogan-Yildirim Z; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA., Lee MK; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA., Curtis SW; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Berke S; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA., Brewer GC; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., McHenry T; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA., El Sergani AM; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA., Anderton J; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA., Mukhopadhyay N; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA., Carlson JC; Department of Biostatistics and Health Data Science, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Beaty T; Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA., Butali A; Department of Oral Pathology, Radiology, & Medicine, College of Dentistry, University of Iowa, Iowa City, IA, USA., Buxo-Martinez CJ; Dental and Craniofacial Genomics Core, School of Dental Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA., Hecht JT; Department of Pediatrics and Pediatric Research Center, McGovern Medical School University of Texas Health, Houston, TX, USA., Liao EC; Division of Plastic, Reconstructive, and Oral Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Craniofacial Innovation, Children's Hospital of Philadelphia Research Institute, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Moreno Uribe LM; Department of Orthodontics, College of Dentistry, University of Iowa, Iowa City, IA, USA., Padilla CD; Department of Pediatrics, College of Medicine, University of the Philippines, Manila, Philippines., Wehby G; Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA, USA., Feingold E; Department of Statistics, College of Science, Oregon State University, Corvallis, OR, USA., Murray JC; Department of Pediatrics, School of Medicine, University of Iowa, Iowa City, IA, USA., Ruczinski I; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA., Leslie-Clarkson EJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Weinberg SM; Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Shaffer JR; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Marazita ML; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: marazita@pitt.edu. |
| Πηγή: | HGG advances [HGG Adv] 2026 Oct 08; Vol. 7 (4), pp. 100672. Date of Electronic Publication: 2026 Sep 10. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Inc Country of Publication: United States NLM ID: 101772885 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2666-2477 (Electronic) Linking ISSN: 26662477 NLM ISO Abbreviation: HGG Adv Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York : Elsevier Inc., [2020]- |
| Ιατρικοί όροι (MeSH): | Cleft Lip*/genetics , Genome-Wide Association Study* , Genetic Predisposition to Disease* , Genetic Loci*, Cleft Palate/genetics ; Interferon Regulatory Factors/genetics ; MafB Transcription Factor/genetics ; Humans ; Polymorphism, Single Nucleotide ; Phenotype |
| Περίληψη: | Orofacial clefts (OFCs) are the most common craniofacial birth defect and comprise a diverse group of traits with complex and heterogeneous etiologies. Genetic studies of OFCs typically approach this diversity by stratifying cases into broad diagnostic classes, including cleft lip (CL), cleft palate (CP), and cleft lip with palate (CLP). Although this strategy has yielded important insights into OFC risk, it ignores the phenotypic heterogeneity within each subtype. CL exhibits marked phenotypic variability, involving differences in alveolar involvement, laterality, and sidedness that may reflect distinct etiologies. Given this phenotypic diversity within CL, we assembled a multi-ancestry cohort of 837 nonsyndromic CL case-parent trios with whole-genome sequencing and detailed phenotyping. We performed genome-wide association scans (GWASs) via transmission disequilibrium tests for CL overall and for 14 CL subtypes defined by involvement of the alveolus (with and without), laterality (uni- and bilateral), and sidedness (left and right). We identified four genome-wide significant loci. Two loci, IRF6 and 8q24.21, were both detected in the overall CL GWAS. PLCB1/PLCB4 and MAFB were detected in GWASs of alveolar cleft involvement and CL left-sidedness, respectively. These subtype-specific associations were followed by case-only comparisons that reflect the presence or absence of alveolus cleft or left-sided bias of CL to confirm the specificity of the association signal to the particular subtype. Our results provide evidence of within-class CL-subtype-specific genetic links for loci previously discussed in the context of primary OFC classes and demonstrate the value of granular OFC subtype characterization to capture trait-specific associations. (Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests The authors declare no competing interests. |
| Σχόλια: | Update of: medRxiv. 2026 Mar 17:2026.03.15.26348427. doi: 10.64898/2026.03.15.26348427.. (PMID: 41891029) |
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| Grant Information: | R01 DE031855 United States DE NIDCR NIH HHS; T32 GM149422 United States GM NIGMS NIH HHS; T90 DE030853 United States DE NIDCR NIH HHS; R01 DE032319 United States DE NIDCR NIH HHS; R01 DE032122 United States DE NIDCR NIH HHS; R01 DE008559 United States DE NIDCR NIH HHS; R01 DE028342 United States DE NIDCR NIH HHS; R00 DE024571 United States DE NIDCR NIH HHS; S10 OD028483 United States OD NIH HHS; R01 DE016148 United States DE NIDCR NIH HHS |
| Contributed Indexing: | Keywords: Gabriella Miller Kids First; alveolus cleft; cleft lip; genetic modifier; left unilateral cleft; trio-based GWAS |
| Substance Nomenclature: | 0 (Interferon Regulatory Factors) 0 (IRF6 protein, human) 0 (MafB Transcription Factor) 0 (MAFB protein, human) |
| Entry Date(s): | Date Created: 20260911 Date Completed: 20261008 Latest Revision: 20261014 |
| Update Code: | 20261014 |
| PubMed Central ID: | PMC13654461 |
| DOI: | 10.1016/j.xhgg.2026.100672 |
| PMID: | 42723286 |
| Βάση Δεδομένων: | MEDLINE |
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