The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation
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 explo...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2021.626403/full |
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| language |
English |
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Article |
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DOAJ |
| author |
Karlijne Indencleef Karlijne Indencleef Hanne Hoskens Hanne Hoskens Myoung Keun Lee Julie D. White Chenxing Liu Ryan J. Eller Sahin Naqvi Sahin Naqvi George L. Wehby Lina M. Moreno Uribe Jacqueline T. Hecht Ross E. Long Kaare Christensen Frederic W. Deleyiannis Susan Walsh Mark D. Shriver Stephen Richmond Joanna Wysocka Joanna Wysocka Hilde Peeters John R. Shaffer John R. Shaffer Mary L. Marazita Mary L. Marazita Greet Hens Seth M. Weinberg Seth M. Weinberg Seth M. Weinberg Peter Claes Peter Claes Peter Claes |
| spellingShingle |
Karlijne Indencleef Karlijne Indencleef Hanne Hoskens Hanne Hoskens Myoung Keun Lee Julie D. White Chenxing Liu Ryan J. Eller Sahin Naqvi Sahin Naqvi George L. Wehby Lina M. Moreno Uribe Jacqueline T. Hecht Ross E. Long Kaare Christensen Frederic W. Deleyiannis Susan Walsh Mark D. Shriver Stephen Richmond Joanna Wysocka Joanna Wysocka Hilde Peeters John R. Shaffer John R. Shaffer Mary L. Marazita Mary L. Marazita Greet Hens Seth M. Weinberg Seth M. Weinberg Seth M. Weinberg Peter Claes Peter Claes Peter Claes The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation Frontiers in Genetics NSCL/P endophenotype genetics facial morphology ALSPAC |
| author_facet |
Karlijne Indencleef Karlijne Indencleef Hanne Hoskens Hanne Hoskens Myoung Keun Lee Julie D. White Chenxing Liu Ryan J. Eller Sahin Naqvi Sahin Naqvi George L. Wehby Lina M. Moreno Uribe Jacqueline T. Hecht Ross E. Long Kaare Christensen Frederic W. Deleyiannis Susan Walsh Mark D. Shriver Stephen Richmond Joanna Wysocka Joanna Wysocka Hilde Peeters John R. Shaffer John R. Shaffer Mary L. Marazita Mary L. Marazita Greet Hens Seth M. Weinberg Seth M. Weinberg Seth M. Weinberg Peter Claes Peter Claes Peter Claes |
| author_sort |
Karlijne Indencleef |
| title |
The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation |
| title_short |
The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation |
| title_full |
The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation |
| title_fullStr |
The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation |
| title_full_unstemmed |
The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation |
| title_sort |
intersection of the genetic architectures of orofacial clefts and normal facial variation |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Genetics |
| issn |
1664-8021 |
| publishDate |
2021-02-01 |
| description |
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. |
| topic |
NSCL/P endophenotype genetics facial morphology ALSPAC |
| url |
https://www.frontiersin.org/articles/10.3389/fgene.2021.626403/full |
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doaj-b44ba2f0b8b04c2ab9758cb8e66b33912021-02-22T05:43:26ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-02-011210.3389/fgene.2021.626403626403The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial VariationKarlijne Indencleef0Karlijne Indencleef1Hanne Hoskens2Hanne Hoskens3Myoung Keun Lee4Julie D. White5Chenxing Liu6Ryan J. Eller7Sahin Naqvi8Sahin Naqvi9George L. Wehby10Lina M. Moreno Uribe11Jacqueline T. Hecht12Ross E. Long13Kaare Christensen14Frederic W. Deleyiannis15Susan Walsh16Mark D. Shriver17Stephen Richmond18Joanna Wysocka19Joanna Wysocka20Hilde Peeters21John R. Shaffer22John R. Shaffer23Mary L. Marazita24Mary L. Marazita25Greet Hens26Seth M. Weinberg27Seth M. Weinberg28Seth M. Weinberg29Peter Claes30Peter Claes31Peter Claes32Department of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, BelgiumMedical Imaging Research Center, UZ Leuven, Leuven, BelgiumMedical Imaging Research Center, UZ Leuven, Leuven, BelgiumDepartment of Human Genetics, KU Leuven, Leuven, BelgiumDepartment of Oral Biology, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Anthropology, Pennsylvania State University, State College, PA, United StatesDepartment of Oral Biology, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, United StatesDepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Genetics, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA, United States0Department of Orthodontics & The Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, Iowa City, IA, United States1Department of Pediatrics, McGovern Medical School and School of Dentistry, UT Health at Houston, Houston, TX, United States2Lancaster Cleft Palate Clinic, Lancaster, PA, United States3Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark4UCHealth Medical Group, Colorado Springs, CO, United StatesDepartment of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, United StatesDepartment of Anthropology, Pennsylvania State University, State College, PA, United States5Applied Clinical Research and Public Health, School of Dentistry, Cardiff University, Cardiff, United KingdomDepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, United States6Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Human Genetics, KU Leuven, Leuven, BelgiumDepartment of Oral Biology, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, United States7Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Oral Biology, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, United States7Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States8Department of Otorhinolaryngology, KU Leuven, Leuven, BelgiumDepartment of Oral Biology, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, United States7Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States9Department of Anthropology, University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Electrical Engineering, ESAT/PSI, KU Leuven, Leuven, BelgiumMedical Imaging Research Center, UZ Leuven, Leuven, BelgiumDepartment of Human Genetics, KU Leuven, Leuven, BelgiumUnaffected 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.https://www.frontiersin.org/articles/10.3389/fgene.2021.626403/fullNSCL/Pendophenotypegeneticsfacial morphologyALSPAC |