{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T07:04:29Z","timestamp":1784012669281,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,10]]},"group-title":"Dentistry and Oral Medicine","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institutes of Health: National Institute for Dental and Craniofacial Research","award":["U01DE025046"],"award-info":[{"award-number":["U01DE025046"]}]},{"name":"National Institutes of Health: National Institute for Dental and Craniofacial Research","award":["R01DE034410"],"award-info":[{"award-number":["R01DE034410"]}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"crossref","award":["X01HG010871"],"award-info":[{"award-number":["X01HG010871"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  We conducted a multi-ancestry genome-wide association study (GWAS) of developmental defects of enamel (DDE) in the primary dentition among 6,061 U.S. preschool-aged children (3\u20135 years). We investigated four DDE phenotypes (demarcated opacities, diffuse opacities, hypoplastic defects, and a combined DDE trait) leveraging main-effect models, joint gene-sex interaction testing (2df), and sex-stratified analyses. SNP-based heritability for the combined DDE trait was estimated at 20%, with concordance analyses robustly supporting a genetic etiology. We identified 39 unique genome-wide significant loci (\n                  <jats:italic>P<\/jats:italic>\n                  &lt;5\u00d710\u25a1\u25a1), with five surpassing a study-wide Bonferroni-corrected statistical significance criterion (\n                  <jats:italic>P<\/jats:italic>\n                  &lt;1.25\u00d710\u25a1\u25a1), including\n                  <jats:italic>Y RNA<\/jats:italic>\n                  and\n                  <jats:italic>ALDH1A1<\/jats:italic>\n                  . The main-effect GWAS identified 20 loci, including\n                  <jats:italic>HBS1L<\/jats:italic>\n                  and\n                  <jats:italic>MYB<\/jats:italic>\n                  , genes regulating hematopoiesis with plausible roles in amelogenesis. Joint test and sex-stratified analyses revealed 19 additional loci, including\n                  <jats:italic>ALDH1A1<\/jats:italic>\n                  ,\n                  <jats:italic>TENM2<\/jats:italic>\n                  , and\n                  <jats:italic>DLGAP2<\/jats:italic>\n                  , demonstrating sex-specific heterogeneity. Nineteen loci exhibited sex-specific differences after Bonferroni correction (P&lt;2x10\n                  <jats:sup>-3<\/jats:sup>\n                  ), including genes involved in retinoic acid signaling (\n                  <jats:italic>ALDH1A1<\/jats:italic>\n                  ), odontogenesis (\n                  <jats:italic>TENM2<\/jats:italic>\n                  ), and neurodevelopment (\n                  <jats:italic>DLGAP2<\/jats:italic>\n                  ,\n                  <jats:italic>CDH10<\/jats:italic>\n                  ). Pathway enrichment highlighted ectodermal and synapse organization networks, suggesting shared etiological mechanisms between DDE and systemic conditions like neurofibromatosis and autism spectrum disorder. Notably, no locus generalized in an external GWAS of permanent dentition DDE, underscoring fundamental biological differences in the genetic architectures governing primary versus permanent enamel formation. Crucially, a comprehensive cross-trait pleiotropy lookup against early childhood caries (ECC) revealed no shared genetic architecture, supporting the notion that the established clinical and epidemiological association between DDE and ECC is likely driven by structural defects increasing caries lesion susceptibility rather than genetic pleiotropy. By integrating gene-sex interaction testing, this study offers novel insights into the complex, sexually dimorphic genetic etiology of DDE and augments the biological evidence base that can support the development of precision pediatric dentistry.\n                <\/jats:p>","DOI":"10.64898\/2026.07.06.26355672","type":"posted-content","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T23:15:11Z","timestamp":1783725311000},"source":"Crossref","is-referenced-by-count":0,"title":["Genomic basis of developmental defects of enamel and sex-specific effects"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1604-082X","authenticated-orcid":false,"given":"P","family":"Shrestha","sequence":"first","affiliation":[{"name":"Department of Pediatric Dentistry and Dental Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA"},{"name":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6380-1735","authenticated-orcid":false,"given":"M","family":"Graff","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Statistics and Actuarial Science, School of Computing and Data Science, The University of Hong Kong, Pokfulam Road, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HS","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry and Dental Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"KN","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry and Dental Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Khanna","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry and Dental Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1044-8162","authenticated-orcid":false,"given":"CL","family":"Avery","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3583-8239","authenticated-orcid":false,"given":"HM","family":"Highland","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2127-5212","authenticated-orcid":false,"given":"J","family":"Ginnis","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry and Dental Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2292-416X","authenticated-orcid":false,"given":"MA","family":"Simancas-Pallares","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry and Dental Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0237-9416","authenticated-orcid":false,"given":"AG","family":"Ferreira Zandon\u00e1","sequence":"additional","affiliation":[{"name":"Department of Restorative and Prosthetic Sciences, The Ohio State University College of Dentistry, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6455-9522","authenticated-orcid":false,"given":"RN","family":"Alotaibi","sequence":"additional","affiliation":[{"name":"Dental Health Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DY","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7869-2057","authenticated-orcid":false,"given":"JS","family":"Preisser","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4065-6341","authenticated-orcid":false,"given":"GD","family":"Slade","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry and Dental Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2648-2832","authenticated-orcid":false,"given":"ML","family":"Marazita","sequence":"additional","affiliation":[{"name":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine; Department of Human Genetics, School of Public Health; University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8903-0366","authenticated-orcid":false,"given":"KE","family":"North","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA"},{"name":"Border Health Research Center, School of Public Health, UTHealth Houston, Brownsville, Texas, USA"},{"name":"Department of Internal Medicine, McGovern Medical School, UTHealth Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1290-7251","authenticated-orcid":false,"given":"K","family":"Divaris","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry and Dental Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA"},{"name":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071323151815000_2026.07.06.26355672v1.1","unstructured":"AAPD. 2025. Caries-risk assessment and management for infants, children, and adolescents. In: The Reference Manual of Pediatric Dentistry. American Academy of Pediatric Dentistry. p. 325\u201331."},{"issue":"2","key":"2026071323151815000_2026.07.06.26355672v1.2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1159\/000522642","article-title":"Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts","volume":"87","year":"2022","journal-title":"Hum Hered"},{"key":"2026071323151815000_2026.07.06.26355672v1.3","doi-asserted-by":"publisher","DOI":"10.1177\/0022034512444929"},{"key":"2026071323151815000_2026.07.06.26355672v1.4","doi-asserted-by":"publisher","DOI":"10.1177\/0022034512447951"},{"key":"2026071323151815000_2026.07.06.26355672v1.5","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph17186591"},{"issue":"11","key":"2026071323151815000_2026.07.06.26355672v1.6","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1111\/jcpe.13538","article-title":"Sex-specific genetic factors affect the risk of early-onset periodontitis in Europeans","volume":"48","year":"2021","journal-title":"J Clin Periodontol"},{"issue":"1","key":"2026071323151815000_2026.07.06.26355672v1.7","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s00784-017-2115-1","article-title":"Significance of genetic variations in developmental enamel defects of primary dentition in Polish children","volume":"22","year":"2018","journal-title":"Clin Oral Investig"},{"key":"2026071323151815000_2026.07.06.26355672v1.8","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/978-1-4939-9012-2_39","article-title":"Measurement of Early Childhood Oral Health for Research Purposes: Dental Caries Experience and Developmental Defects of the Enamel in the Primary Dentition","volume":"1922","year":"2019","journal-title":"Methods Mol Biol"},{"key":"2026071323151815000_2026.07.06.26355672v1.9","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.12437"},{"key":"2026071323151815000_2026.07.06.26355672v1.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M710565200"},{"key":"2026071323151815000_2026.07.06.26355672v1.11","doi-asserted-by":"publisher","DOI":"10.1046\/j.0960-7439 .2001.00318.x"},{"key":"2026071323151815000_2026.07.06.26355672v1.12","doi-asserted-by":"publisher","DOI":"10.1159\/000099183"},{"key":"2026071323151815000_2026.07.06.26355672v1.13","doi-asserted-by":"publisher","DOI":"10.1007\/s00784-013-1054-8"},{"key":"2026071323151815000_2026.07.06.26355672v1.14","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22965"},{"key":"2026071323151815000_2026.07.06.26355672v1.15","doi-asserted-by":"crossref","unstructured":"Li YR , Keating BJ . 2014. Trans-ethnic genome-wide association studies: Advantages and challenges of mapping in diverse populations. Genome Med. 6(10).","DOI":"10.1186\/s13073-014-0091-5"},{"key":"2026071323151815000_2026.07.06.26355672v1.16","doi-asserted-by":"crossref","unstructured":"Lunardelli SE , Lunardelli AN , Martins LGT , Traebert E , Traebert J . 2024. Prenatal, neonatal and postnatal factors and the developmental defects of dental enamel. Rev Paul Pediatr. 42. [accessed 2025 Nov 4]. https:\/\/pubmed.ncbi.nlm.nih.gov\/37646751\/.","DOI":"10.1590\/1984-0462\/2024\/42\/2022226"},{"key":"2026071323151815000_2026.07.06.26355672v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.20546"},{"key":"2026071323151815000_2026.07.06.26355672v1.18","doi-asserted-by":"crossref","unstructured":"Marshman Z , Rodd HD . 2015. The Psychosocial Impacts of Developmental Enamel Defects in Children and Young People. In: Planning and Care for Children and Adolescents with Dental Enamel Defects: Etiology, Research and Contemporary Management. Springer, Berlin, Heidelberg. p. 85\u201397.","DOI":"10.1007\/978-3-662-44800-7_7"},{"issue":"1","key":"2026071323151815000_2026.07.06.26355672v1.19","doi-asserted-by":"crossref","first-page":"65","DOI":"10.15644\/asc50\/1\/9","article-title":"Developmental Defects of Enamel in Children with Intellectual Disability","volume":"50","year":"2016","journal-title":"Acta Stomatol Croat"},{"key":"2026071323151815000_2026.07.06.26355672v1.20","doi-asserted-by":"crossref","unstructured":"N\u00fa\u00f1ez SM , Chun YHP , Ganss B , Hu Y , Richardson AS , Schmitz JE , Fajardo R , Yang J , Hu JC-C , Simmer JP . 2016. Maturation stage enamel malformations in Amtn and Klk4 null mice. Matrix Biol. 52\u201354:219\u2013233.","DOI":"10.1016\/j.matbio.2015.11.007"},{"key":"2026071323151815000_2026.07.06.26355672v1.21","doi-asserted-by":"crossref","unstructured":"Rasmussen AH , Rasmussen HB , Silahtaroglu A . 2017. The DLGAP family: Neuronal expression, function and role in brain disorders. Mol Brain. 10(1).","DOI":"10.1186\/s13041-017-0324-9"},{"key":"2026071323151815000_2026.07.06.26355672v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2012.06.020"},{"issue":"2","key":"2026071323151815000_2026.07.06.26355672v1.23","first-page":"e187","article-title":"Prevalence of enamel defects in primary and permanent teeth in a group of schoolchildren from Granada (Spain)","volume":"18","year":"2013","journal-title":"Med Oral Patol Oral Cir Bucal"},{"issue":"14","key":"2026071323151815000_2026.07.06.26355672v1.24","doi-asserted-by":"crossref","first-page":"4687","DOI":"10.3390\/app10144687","article-title":"Oral clinical manifestations of neurofibromatosis type 1 in children and adolescents","volume":"10","year":"2020","journal-title":"Appl Sci"},{"issue":"3","key":"2026071323151815000_2026.07.06.26355672v1.25","first-page":"207","article-title":"Comparison of Enamel Defects in the Primary and Permanent Dentitions of Children from a Low-fluoride District in Australia","volume":"33","year":"2011","journal-title":"Pediatr Dent"},{"issue":"3","key":"2026071323151815000_2026.07.06.26355672v1.26","first-page":"280","article-title":"Multi-ancestry Genome-Wide Association Study of Early Childhood Caries","volume":"10","year":"2025","journal-title":"J Dent Res"},{"key":"2026071323151815000_2026.07.06.26355672v1.27","doi-asserted-by":"crossref","unstructured":"Wang T , Li K , Liu H , Luo E . 2022. Focusing on Hippo Pathway in Stem Cells of Oral Origin, Enamel Formation and Periodontium Regeneration. Organogenesis. 18(1).","DOI":"10.1080\/15476278.2022.2082236"},{"key":"2026071323151815000_2026.07.06.26355672v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-016-0009-6"},{"key":"2026071323151815000_2026.07.06.26355672v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu621"},{"key":"2026071323151815000_2026.07.06.26355672v1.30","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-447-0_9"},{"key":"2026071323151815000_2026.07.06.26355672v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0184-y"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.06.26355672","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:15:26Z","timestamp":1784009726000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.07.06.26355672"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,10]]},"references-count":31,"URL":"https:\/\/doi.org\/10.64898\/2026.07.06.26355672","relation":{},"subject":[],"published":{"date-parts":[[2026,7,10]]},"subtype":"preprint"}}