Year: 2025
Type: article
Study design: Observational Study
Abstract: Nonsyndromic orofacial clefts (OFCs) are common, heritable birth defects caused by both genetic and environmental risk factors. Despite the identification of many genetic loci harboring OFC-risk variants, there are many unknown genetic determinants of OFC. Furthermore, while the process of embryonic facial development is well characterized, the molecular mechanisms that underly it are not. This represents a major hurdle in understanding how disruptions in these biological processes result in OFC. Thus, we sought to identify novel OFC-risk loci through a genome-wide multi-ancestry study of five nested OFC phenotypes (isolated cleft lip [CLO], isolated cleft palate [CPO], cleft lip and palate [CLP], cleft lip with/without cleft palate [CL/P], and any cleft [ANY]) representing distinct cleft subtypes to identify subtype-specific signals and grouped types to maximize power to detect shared genetic effects. We performed genome-wide meta-analyses of these five OFC phenotypes from three cohorts totaling >14,000 individuals using METAL. In addition to replicating 13 known OFC-risk loci, we observed novel association in three regions: the 1p36.32 locus (lead variant rs584402, an intergenic variant, pCLO = 3.14e-8), the 7q33 locus (lead variant rs17168118, an intronic variant in CALD1, pCLP = 9.17e-9), and the 16p13.3 locus (lead variant rs77075754, an intronic variant in RBFOX1, pCL/P = 1.53e-9, pANY = 1.93e-9). We also observed a novel association within the known risk locus 8q22.1 that was independent of the previously reported signal (lead variant rs4735314, an intronic variant in ESRP1, pCLP = 1.07e-9, pCL/P = 3.88e-8). Next, we performed multi-tissue TWAS with s-MulTiXcan and identified four overlapping genes with significant genetically predicted transcription associated with OFC risk. These genes also overlapped the genome-wide significant association signals from the meta-analysis, including CALD1 and ESRP1 and known OFC-risk genes TANC2 and NTN1. Each of the newly reported loci has potential regulatory effects, including evidence of craniofacial enhancer activity, that offer new clues as to the molecule mechanisms underlying embryonic facial development.
Source: PLoS Genetics
Authors: Jenna C. Carlson, Xinyi Zhang, Zeynep Erdogan-Yildirim, Terri H. Beaty, Azeez Butali, Carmen J. Buxó, Lord J.J. Gowans, Jacqueline T. Hecht, Ross E. Long, Lina Moreno, Jeffrey C. Murray, Ieda M. Orioli, Carmencita Padilla, George L. Wehby, Eleanor Feingold, Elizabeth J. Leslie-Clarkson, Seth M. Weinberg, Mary L. Marazita, John R. Shaffer
Institutions: University of Pittsburgh, Johns Hopkins University, University of Iowa, University of Puerto Rico, Medical Sciences Campus, University of Puerto Rico System, Kwame Nkrumah University of Science and Technology, The University of Texas Health Science Center at Houston, Universidade Federal do Rio de Janeiro, National Institute on Population Medical Genetics, University of the Philippines System, University of the Philippines Manila, Oregon State University, Emory University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: University of Pittsburgh, National Institutes of Health, Center for Research Computing, University of Pittsburgh, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Dental and Craniofacial Research, National Institute on Minority Health and Health Disparities, Office of Research Infrastructure Programs, National Institutes of Health
Awards: G1018274572, G1071444454, G1252961728, G1319322569, G1482625604, G1546933035, G1608539532, Functional tests of non-coding DNA variants associated with risk for orofacial clefting., G1952764943, G2282176147, GENE MAPPING STUDIES OF ORAL/FACIAL CLEFTS--CHINA/INDIA, G2592393619, International Consortium to Identify Genes and Interactions Controlling Oral Clef, G3025648356, G321227836, G3295005934, G3400707517, G3628905811, Refining the Genetic and Genomic Architecture of Non‐syndromic Orofacial Clefts, MOLECULAR GENETIC EPIDEMIOLOGY OF CLEFT LIP AND PALATE, G4365870516, High-Throughput Computing for Genomics and Bioinformatics Research, G6397938196, G7165246917, Hispanic Alliance for Clinical and Translational Research (Alliance), G8527069233, Genomics of Cleft Palate, G9000008317, G9000075272, G9000086226, G9000149863, G9000156852, G9000189650, G9000268047, G9000329084, G9000331162, Genomic Risk Variants in Orofacial Clefting: Discovery and Functional Validation
OpenAlex ID: W4414648769