Spector, T. D. — Page 2 | Search bioRxiv

bioRxiv2017

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.

genetics↗

bioRxiv2017

The genetics of the human face: identification of large effect single gene variants

In order to discover specific variants with relatively large effects on the human face we have devised an approach to identifying facial features with high heritability. This is based on using twin data to estimate the additive genetic value of each point on a face, as provided by a 3D camera system. In addition, we have used the ethnic difference between East Asian and European faces as a further source of face genetic variation. We use principal components analysis to provide a fine definition of the surface features of human faces around the eyes and of the profile, and chose upper and lower 10% extremes of the most heritable PCs for looking for genetic associations. Using this strategy for the analysis of 3D images of 1832 unique volunteers from the well characterised People of the British Isles study [1, 2] and 1567 unique twin images from the TwinsUK cohort (www.twinsuk.ac.uk), together with genetic data for 500,000 SNPs, we have identified three specific genetic variants with notable effects on facial profiles and eyes.\n\nSignificance statementThe human face is extraordinarily variable and the extreme similarity of the faces of identical twins indicates that most of this variability is genetically determined. This level of genetic variability has probably arisen through natural selection, for example, for recognition of membership of a group or as a consequence of differential mate selection with respect to facial features. We have devised an approach to identifying specific genetic effects on particular facial features. This should enable the understanding, eventually at the molecular level, of the nature of this extraordinary genetic variability, which is such an important feature of our everyday human interactions.\n\nAuthor ContributionsWFB conceived the project. BW and TD organised collection of PoBI data and KH, DJMC, DM, AB and WFB assisted in data collection. TDS, PH and AN collected TwinsUK data. WPK and WJC conducted image registration analysis under supervision of JK. DJMC analysed registered image data and genetic data under supervision of WFB. WFB and DJMC wrote the manuscript, with WJC and WPK contributing additional technical material. WFB and BW supervised the project.

genetics↗