The human face comprises an assemblage of multiple multifactorial complex traits, each with clear genetic components as well as known environmental factors play key roles in the lifelong development and maturation of facial shape and appearance. Recent advances in methodology for deriving accurate and precise facial traits have allowed for large-scale genomic studies that have provided new insights into the heritability and specific genes involved in normal facial variation. The proposed project entailed genotyping candidate single-nucleotide polymorphisms (SNPs) that might be involved in facial shape in 797 European-derived white (EUR) subjects for whom we had existing three-dimensional facial scans and DNA samples. In fact, we were able to include these subjects in a collaborative large-scale genomewide association study (GWAS) of human facial shape in the EUR population. We conducted genome-wide association metaanalyses of 20 quantitative facial measurements derived from t3D surface images of a total 3118 healthy individuals of EUR ancestry. Subjects were genotyped for almost one million genotyped SNPs and were imputed to the 1000 Genomes reference panel (Phase 3), for almost 35,000,000 total SNPs. Detailed analyses showed heritability of facial trait measurements ranging from 28% - 67%, with horizontal measures being slightly more heritable than vertical or depth measures. Furthermore, for over half of facial traits >90% of narrow-sense heritability can be explained by common genetic variation. We also found high absolute genetic correlation between most traits, indicating large overlap in underlying genetic loci. We observed genomewide significant associations for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genomewide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. In general, there has been limited cross-replication of loci associated with facial shape parameters across different GWAS. Furthermore, environmental influences, sex, and age play major roles in determining facial shape and appearance. This raises significant concerns about the validity and utility of current tests that claim to predict facial appearance from forensic DNA specimens.
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