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Trio-based GWAS reveals novel loci associated with different forms of isolated cleft lip.

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Title: Trio-based GWAS reveals novel loci associated with different forms of isolated cleft lip.
Authors: Herrick N; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA, USA., 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 G; 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, 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; School of Dental Medicine, University of Puerto Rico, San Juan, USA., Hecht JT; Department of Pediatrics and Pediatric Research Center, University of Texas Medical School, Houston, TX, USA., Liao E; Division of Plastic, Reconstructive, and Oral Surgery, Children's Hospital of Philadelphia, Philadelphia, PA.; 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.
Source: MedRxiv : the preprint server for health sciences [medRxiv] 2026 Mar 17. Date of Electronic Publication: 2026 Mar 17.
Publication Type: Journal Article; Preprint
Language: English
Journal Info: Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE
Abstract: 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 (GWAS) 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 additional, new evidence of 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.
Competing Interests: Conflict of Interest: The authors have no conflict of interest to declare.
Comments: Update in: HGG Adv. 2026 Sep 10;7(4):100672. doi: 10.1016/j.xhgg.2026.100672.. (PMID: 42723286)
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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; R03 DE035068 United States DE NIDCR NIH HHS; S10 OD028483 United States OD NIH HHS; R01 DE016148 United States DE NIDCR NIH HHS
Contributed Indexing: Keywords: Alveolus Cleft; Cleft Lip; Gabriella Miller Kids First; Genetic Modifier; Left Unilateral Cleft; Trio-based GWAS
Entry Date(s): Date Created: 20260327 Date Completed: 20260915 Latest Revision: 20260930
Update Code: 20260930
PubMed Central ID: PMC13015659
DOI: 10.64898/2026.03.15.26348427
PMID: 41891029
Database: MEDLINE
Description
DOI:10.64898/2026.03.15.26348427