Impact of low-frequency coding variants on human facial shape.

Area of Science:

• Human Genetics
• Facial Morphology
• Bioinformatics

Background:

• The genetic underpinnings of normal-range facial traits are not fully understood.
• The role of low-frequency genetic variants (minor allele frequency < 1%) in facial shape variation remains largely unexplored.

Purpose of the Study:

• To investigate the contribution of low-frequency coding variants in 8091 genes to multi-dimensional facial shape phenotypes.
• To identify specific genes associated with normal-range facial morphology in a European cohort.

Main Methods:

• Analysis of three-dimensional facial images from 2329 healthy individuals.
• Partitioning the face into 31 segments to model morphology at multiple levels.
• Utilizing MultiSKAT, a multivariate kernel regression, to scan the exome for gene-based associations with facial shape.

Main Results:

• Seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) showed significant associations with facial shape variations in the cheek, chin, nose, and mouth.
• The NECTIN1 gene, particularly the missense variant rs142863092, significantly impacted chin morphology and was predicted to affect protein function.
• Mutations in the zebrafish nectin1a gene demonstrated effects on craniofacial development, specifically altering mandibular cartilage.

Conclusions:

• Low-frequency coding variants play a role in the genetic architecture of normal-range facial shape.
• NECTIN1 is highlighted as a novel gene associated with facial morphology, with implications for craniofacial development and associated syndromes.
• This research expands the understanding of the genetic basis of human facial diversity.