biostudies-literatureLi QLeverhulme TrustIntramural NIH HHSScience and Technology Commission of Shanghai MunicipalityNIDCR NIH HHSAix-Marseille UniversityNational Major Science and Technology Projects of ChinaNational Natural Science Foundation of ChinaWenner-Gren Foundation for Anthropological ResearchHigher Education Discipline Innovation ProjectUniversidad de AntioquiaMinistry of Science and Technology of the People's Republic of ChinaBiotechnology and Biological Sciences Research CouncilNIGMS NIH HHS131-144.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC11789201biostudies-literatureUnknown35(1)Dental morphology varies greatly throughout evolution, including in the human lineage, but little is known about the biology of this variation. Here, we use multiomics analyses to examine the genetics of variation in tooth crown dimensions. In a human cohort with mixed continental ancestry, we detected genome-wide significant associations at 18 genome regions. One region includes EDAR, a gene known to impact dental features in East Asians. Furthermore, we find that EDAR variants increase the mesiodistal diameter of all teeth, following an anterior-posterior gradient of decreasing strength. Among the 17 novel-associated regions, we replicate 7/13 in an independent human cohort and find that 4/12 orthologous regions affect molar size in mice. Two association signals point to compelling candiCurrent biology : CBPITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans.PMC11789201R01 DE028945F30 DE031149BB/I021213/1Z01 DE000707R35 GM119465Hoffman MPCox TCPoloni LBortolini MCCox JCDing LFuentes-Guajardo MAdhikari KNavarro NDelgado MAcuna VCotney JRamirez LMChen YGonzalez-Jose RGallo CPoletti GYang GZheng YLi QPatel VFaux PWentworth Winchester ESteimetz ERothhammer FPeng CRojas WRuiz-Linares AfalsePITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans.Dental morphology varies greatly throughout evolution, including in the human lineage, but little is known about the biology of this variation. Here, we use multiomics analyses to examine the genetics of variation in tooth crown dimensions. In a human cohort with mixed continental ancestry, we detected genome-wide significant associations at 18 genome regions. One region includes EDAR, a gene known to impact dental features in East Asians. Furthermore, we find that EDAR variants increase the mesiodistal diameter of all teeth, following an anterior-posterior gradient of decreasing strength. Among the 17 novel-associated regions, we replicate 7/13 in an independent human cohort and find that 4/12 orthologous regions affect molar size in mice. Two association signals point to compelling candi2025-01-01T00:00:00Z2025 Jan2026-06-06T20:04:13.845Z2026-06-04T03:14:56.231ZS-EPMC117892013967215710.1016/j.cub.2024.11.027