The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation

Frontiers in Genetics

Jacqueline T. Hecht¹  Lina M. Moreno Uribe²  Ross E. Long³  Kaare Christensen⁴  Frederic W. Deleyiannis⁵  Susan Walsh⁶  Hilde Peeters⁸  Greet Hens⁹  Seth M. Weinberg⁹  Stephen Richmond^1,12  Julie D. White^1,12  Ryan J. Eller^1,13  Mark D. Shriver^1,13  Joanna Wysocka^1,14  Sahin Naqvi^1,16  George L. Wehby^1,17  Hanne Hoskens^1,18  Mary L. Marazita^1,19  John R. Shaffer^1,19  Myoung Keun Lee^1,19  Chenxing Liu^1,19  Karlijne Indencleef^2,20  Peter Claes^2,20 

[1] The Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA, United States;;0Department of Orthodontics &1Department of Pediatrics, McGovern Medical School and School of Dentistry, UT Health at Houston, Houston, TX, United States;2Lancaster Cleft Palate Clinic, Lancaster, PA, United States;3Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark;4UCHealth Medical Group, Colorado Springs, CO, United States;5Applied Clinical Research and Public Health, School of Dentistry, Cardiff University, Cardiff, United Kingdom;6Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United States;7Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States;8Department of Otorhinolaryngology, KU Leuven, Leuven, Belgium;9Department of Anthropology, University of Pittsburgh, Pittsburgh, PA, United States;Department of Anthropology, Pennsylvania State University, State College, PA, United States;Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, United States;Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, United States;Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, Belgium;Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States;Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA, United States;Department of Human Genetics, KU Leuven, Leuven, Belgium;Department of Oral Biology, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, United States;Medical Imaging Research Center, UZ Leuven, Leuven, Belgium;

关键词: NSCL/P;    endophenotype;    genetics;    facial morphology;    ALSPAC;   

DOI  :  10.3389/fgene.2021.626403

来源: DOAJ

【 摘 要 】

Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance (p ≤ 0.05) and 52 segments at Bonferroni corrected significance (p < 1.2 × 10–3), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated (p < 5 × 10–8) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold (p < 8.47 × 10–10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.

【 授权许可】

Unknown