Over 250 novel associations with human morphological traits. N. Eriksson, C. B. Do, J. Y. Tung, A. K. Kiefer, D. A. Hinds, J. L. Mountain, U. Francke 23andMe, Mountain View, CA.
External morphological features are by definition visible and are typically easy to measure. They also generally happen to be highly heritable. As such, they have played a fundamental role in the development of the field of genetics. As morphological traits have frequently been the target of natural selection, their genetics may also provide clues into our evolutionary history. Many rare diseases include dysmorphologic features among their symptoms. However, aside from height and BMI, currently little is known about the genetics of common variation in human morphology. Here we present a series of genome-wide association studies across 18 self-reported morphological traits in a total of over 55,000 people of European ancestry from the customer base of 23andMe. The phenotypes studied include hair traits (baldness, unibrow, hair curl, upper and lower back hair, widows peak), as well as many soft tissue and skeletal traits (chin dimple, nose shape, dimples, earlobe attachment, nose-wiggling ability, the presence of a gap between the top incisors, joint hypermobility, finger and toe relative lengths, arch height, foot direction, height-normalized shoe size). Across the 18 phenotypes, we find a total of 281 genome-wide significant associations (including 53 for unibrow and 29 each for hair curl and chin dimple). Almost all of these associations are novel; we believe this is the largest set of novel associations ever described in a single report. Many of these SNPs show pleiotropic effects, e.g., a SNP near GDF5 is associated with hypermobility, arch height, relative toe length, shoe size, and foot direction; another near AUTS is associated with both back hair and baldness. Nearby genes are significantly enriched to be transcription factors (p<1e-14) and to be involved in rare disorders that cause cleft palate, ear, limb, or skull abnormalities (p<1e-7). A SNP near ZEB2 is associated with both widows peak and chin dimple; mutations in ZEB2 cause Mowat-Wilson syndrome, which includes distinctive facial features such as a pronounced chin. Morphology-associated SNPs are also enriched within regions that have been identified as undergoing selection since the divergence from Neanderthals (18 associations in 11 regions, p = 4e-5). The abundance of these SNPs, which include the ZEB2 and GDF5 associations above, suggest that physical traits may have played a significant role in driving the natural selection processes that gave rise to modern humans.
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