TY - JOUR T1 - Candidate gene scan for Single Nucleotide Polymorphisms involved in the determination of normal variability in human craniofacial morphology JF - bioRxiv DO - 10.1101/060814 SP - 060814 AU - Mark Barash AU - Philipp E. Bayer AU - Angela van Daal Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/07/20/060814.abstract N2 - BackgroundDespite intensive research on genetics of the craniofacial morphology using animal models and human craniofacial syndromes, the genetic variation that underpins normal human facial appearance is still largely unknown. Recent development of novel digital methods for capturing the complexity of craniofacial morphology in conjunction with high-throughput genotyping methods, show great promise for unravelling the genetic basis of such a complex trait. Better understanding of the craniofacial genetics would allow development of novel tools for medical diagnostics of craniofacial syndromes as well as prediction of the facial appearance for forensic and intelligence use.ResultsWe selected 1,319 candidate craniofacial genetic markers and previously described pigmentation polymorphisms as well as additional 4,732 markers in linkage disequilibrium (LD) with candidate markers, which were subsequently genotyped using massively parallel sequencing. We manually allocated 32 craniofacial landmarks and calculated 92 craniofacial distances from 3-Dimentional (3D) facial scans and made six direct cranial measurements of 587 volunteers. We also recorded information on two facial traits (eyelid and ear lobe) and calculated ten principal components, based on all the craniofacial measurements. Genetic association between 104 craniofacial phenotypes and 3,073 genetic markers were tested. Following application of a genomic wide association study (GWAS) p-value threshold of 5.00E-08, 45 single nucleotide polymorphisms (SNPs) in 27 genes and 13 intergenic regions were associated with 11 craniofacial traits. Following subsequent application of an over-conservative Bonferroni correction, associations were observed between 8 craniofacial traits and 12 SNPs located in 12 genes and intergenic regions. We report all the significant associations that reached the 5.00E-08 p-value threshold as we believe this threshold is conservative enough to avoid or at least significantly reduce potentially spurious associations. Majority of associations were in novel genes, while one SNP was in the PAX3 gene that was previously linked to normal variation in craniofacial morphology. Another two polymorphisms were found in the COL11A1 gene, which was previously linked to normal variation in craniofacial morphology, including confirmation of one of the associated SNPs. Associations of the pigmentation traits in this study have fully confirmed previously published results.ConclusionsThis study identified the greatest number of genetic variants associated with normal variation of craniofacial morphology to date by using a candidate gene approach. These results enhance our understanding of the genetics that determines normal variation in craniofacial morphology and will also be of particular value in the forensic field to allow prediction of a person’s appearance from a DNA sample. ER -