Journal article
Trio-based GWAS reveals loci associated with different forms of isolated cleft lip
HGG advances, Vol.7(4), 100672
09/10/2026
DOI: 10.1016/j.xhgg.2026.100672
PMCID: PMC13654461
PMID: 42723286
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 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.
Details
- Title: Subtitle
- Trio-based GWAS reveals loci associated with different forms of isolated cleft lip
- Creators
- Noah Herrick - International Craniofacial InstituteZeynep Erdogan-Yildirim - University of PittsburghMyoung Keun Lee - University of PittsburghSarah W Curtis - Emory UniversitySeth Berke - Princeton UniversityGrace Brewer - Emory UniversityToby McHenry - University of PittsburghAhmed M El Sergani - University of PittsburghJoel Anderton - University of PittsburghNandita Mukhopadhyay - University of PittsburghJenna C Carlson - University of PittsburghTerri Beaty - Johns Hopkins UniversityAzeez Butali - University of IowaCarmen J Buxo-Martinez - Dental and Craniofacial Genomics Core, School of Dental Medicine, University of Puerto Rico, San Juan, USAJacqueline T Hecht - Department of Pediatrics and Pediatric Research Center, University of Texas Medical School, Houston, TX, USAEric Liao - Children's Hospital of PhiladelphiaLina M Moreno Uribe - University of IowaCarmencita D Padilla - University of the Philippines ManilaGeorge Wehby - University of Iowa, Health Management and PolicyEleanor Feingold - Oregon State UniversityJeffrey C Murray - University of IowaIngo Ruczinski - Johns Hopkins UniversityElizabeth J Leslie-Clarkson - Advisory Board Company (United States)Seth M Weinberg - University of North Carolina at Chapel HillJohn R Shaffer - University of PittsburghMary L Marazita - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- HGG advances, Vol.7(4), 100672
- DOI
- 10.1016/j.xhgg.2026.100672
- PMID
- 42723286
- PMCID
- PMC13654461
- NLM abbreviation
- HGG Adv
- ISSN
- 2666-2477
- eISSN
- 2666-2477
- Publisher
- Elsevier
- Grant note
- University of Pittsburgh Center for Research Computing: X01-DE030062, X01-DE032472, T32-GM149422, R01-DE032122, R01-DE032319, R01-DE016148, R01-DE031855, R01-DE008559, R01-DE028342, R01-DE028300, R00-DE024571 NIH: SCR_022735
We express our sincere gratitude to all the individuals and families that participated in these research studies. This work was funded by grants from the National Institutes of Health (T90-DE030853; N.H. and Z.E.-Y.); X01-HL132363 (M.L.M. and E.F.); X01-HL136465 (M.L.M. and E.F.); X01-HD100701 (E.J.L.-C., M.L.M., and J.C.M.); X01-DE030062 (M.L.M. and E.F.); X01-DE032472 (M.L.M. and E.J.L.-C.); T32-GM149422 (G.C.B.); R01-DE032122 (J.R.S.); R01-DE032319 (M.L.M.); R01-DE016148 (M.L.M. and S.M.W.); R01-DE031855 (I.R. and M.L.M.); R01-DE008559 (J.C.M. and M.L.M.); R01-DE028342 (E.J.L.-C.); R01-DE028300 (A.B.); and R00-DE024571 (C.J.B.-M.). This research was supported in part by the University of Pittsburgh Center for Research Computing and Data (RRID: SCR_022735) through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483.
- Language
- English
- Electronic publication date
- 09/10/2026
- Academic Unit
- Preventive and Community Dentistry; Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Health Management and Policy; Stead Family Department of Pediatrics; Epidemiology; Economics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985224347502771
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