Novel genetic loci affecting facial shape variation in humans

Xiong, Ziyi; Dankova, Gabriela; Howe, Laurence J.; Lee, Myoung Keun; Hysi, Pirro G.; de Jong, Markus A.; Zhu, Gu; Adhikari, Kaustubh; Li, Dan; Li, Yi; Pan, Bo; Feingold, Eleanor; Marazita, Mary L.; Shaffer, John R.; McAloney, Kerrie; Xu, Shu-Hua; Jin, Li; Wang, Sijia; de Vrij, Femke M. S.; Lendemeijer, Bas; Richmond, Stephen; Zhurov, Alexei; Lewis, Sarah; Sharp, Gemma C.; Paternoster, Lavinia; Thompson, Holly; Gonzalez-Jose, Rolando; Bortolini, Maria Catira; Canizales-Quinteros, Samuel; Gallo, Carla; Poletti, Giovanni; Bedoya, Gabriel; Rothhammer, Francisco; Uitterlinden, André G.; Ikram, M. Arfan; Wolvius, Eppo; Kushner, Steven A.; Nijsten, Tamar E. C.; Palstra, Robert-Jan T. S.; Boehringer, Stefan; Medland, Sarah E.; Tang, Kun; Ruiz-Linares, Andrés; Martin, Nicholas G.; Spector, Timothy D.; Stergiakouli, Evie; Weinberg, Seth M.; Liu, Fan and Kayser, Manfred (2019). Novel genetic loci affecting facial shape variation in humans. eLife, 8 pp. 1–32.



The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p<5x10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7,917 individuals confirmed 10 loci including 6 unreported ones (padjusted<2.1x10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.

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