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Abstract
The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF < 1%) in 8091 genes on multi-dimensional facial shape phenotypes in a European cohort of 2329 healthy individuals. Using three-dimensional images, we partitioned the full face into 31 hierarchically arranged segments to model facial morphology at multiple levels, and generated multi-dimensional phenotypes representing the shape variation within each segment. We used MultiSKAT, a multivariate kernel regression approach to scan the exome for face-associated low-frequency variants in a gene-based manner. After accounting for multiple tests, seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with shape variation of the cheek, chin, nose and mouth areas. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. The missense variant rs142863092 in NECTIN1 had a significant effect on chin morphology and was predicted bioinformatically to have a deleterious effect on protein function. Notably, NECTIN1 is an established craniofacial gene that underlies a human syndrome that includes a mandibular phenotype. We further showed that nectin1a mutations can affect zebrafish craniofacial development, with the size and shape of the mandibular cartilage altered in mutant animals. Findings from this study expanded our understanding of the genetic basis of normal-range facial shape by highlighting the role of low-frequency coding variants in several novel genes.
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1 University of Pittsburgh, Department of Human Genetics, Graduate School of Public Health, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000)
2 Harvard School of Dental Medicine, Department of Oral Biology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia (GRID:grid.412149.b) (ISNI:0000 0004 0608 0662)
3 KU Leuven, Department of Human Genetics, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884); UZ Gasthuisberg, Medical Imaging Research Center, Leuven, Belgium (GRID:grid.410569.f) (ISNI:0000 0004 0626 3338)
4 University of Pittsburgh, Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000)
5 KU Leuven, Department of Electrical Engineering, ESAT/PSI, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884)
6 University of Texas McGovern Medical Center, Department of Pediatrics, Houston, USA (GRID:grid.267308.8) (ISNI:0000 0000 9206 2401)
7 University of Iowa, Department of Health Management and Policy, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294)
8 University of Iowa, Department of Orthodontics, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294)
9 University of Washington, Department of Pediatrics, Seattle Children’s Craniofacial Center, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657)
10 University of Pittsburgh, Department of Human Genetics, Graduate School of Public Health, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000); University of Pittsburgh, Department of Biostatistics, Graduate School of Public Health, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000)
11 University of Pittsburgh, Department of Human Genetics, Graduate School of Public Health, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000); University of Pittsburgh, Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000)
12 KU Leuven, Department of Human Genetics, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884); KU Leuven, Department of Electrical Engineering, ESAT/PSI, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884)
13 Massachusetts General Hospital, Shriners Hospital, Department of Surgery, Center for Regenerative Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924)