Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers.

The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study (GWAS) meta-analysis of 8,246 European individuals, we identified 203 genome-wide significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses find that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In sum, our analyses provide insights for understanding how complex morphological traits are shaped by both individual and coordinated genetic actions.

A proper understanding of population genetic stratification--differences in individual ancestry within a population--is crucial in attempts to find genes for complex traits through association mapping. We report on genomewide typing of approximately 10,000 single-nucleotide polymorphisms in 297 individuals, to explore population structure in Europeans of known and unknown ancestry. The results reveal the presence of several significant axes of stratification, most prominently in a northern-southeastern trend, but also along an east-west axis. We also demonstrate the selection and application of EuroAIMs (European ancestry informative markers) for ancestry estimation and correction. The Coriell Caucasian and CEPH (Centre d'Etude du Polymorphisme Humain) Utah sample panels, often used as proxies for European populations, are found to reflect different subsets of the continent's ancestry.

Changes in potential regulatory elements are thought to be key drivers of phenotypic divergence. However, identifying changes to regulatory elements that underlie humanspecific traits has proven very challenging. Here, we use 63 reconstructed and experimentally measured DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that likely emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes associated with face and vocal tract anatomy went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face-and voiceassociated genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract.

Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 600 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum p = 4.73×10-8) and two AD-related phenotypes: flushing response (minimum p = 4.75×10-26) and maximum drinks in a 24-hour period (minimum p = 1.54×10-16). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9% and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females – despite familial enrichment for AD – for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally-mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor.