{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:34:20Z","timestamp":1790760860520,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"3-4","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genetic Epidemiology"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Nonsyndromic orofacial clefts\u00a0(OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL\/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt\u2010OFC) multiethnic study.genome\u2010wide association studies\u00a0were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL\/P phenotype. Five novel genome\u2010wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009\u2264\u20091.0E\u221205) within previously confirmed OFC loci\u2014\n                    <jats:italic>PAX7<\/jats:italic>\n                    ,\n                    <jats:italic>IRF6<\/jats:italic>\n                    ,\n                    <jats:italic>FAM49A<\/jats:italic>\n                    ,\n                    <jats:italic>DCAF4L2<\/jats:italic>\n                    , 8q24.21,\n                    <jats:italic>ARID3B, NTN1<\/jats:italic>\n                    ,\n                    <jats:italic>TANC2<\/jats:italic>\n                    and the\n                    <jats:italic>WNT9B:WNT3<\/jats:italic>\n                    gene cluster\u2014were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft\u2010 or family\u2010specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes.\n                  <\/jats:p>","DOI":"10.1002\/gepi.22447","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T10:39:40Z","timestamp":1645526380000},"page":"182-198","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Genome\u2010wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7117-9536","authenticated-orcid":false,"given":"Nandita","family":"Mukhopadhyay","sequence":"first","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of Dental Medicine, Center for Craniofacial and Dental Genetics University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Feingold","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of Dental Medicine, Center for Craniofacial and Dental Genetics University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Biostatistics, Graduate School of Public Health University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Human Genetics, Graduate School of Public Health University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Moreno\u2010Uribe","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, The Iowa Institute for Oral Health Research, College of Dentistry University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Wehby","sequence":"additional","affiliation":[{"name":"Department of Health Management and Policy, College of Public Health University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz Consuelo","family":"Valencia\u2010Ramirez","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Cl\u00ednica Noel  Antioquia Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia P.","family":"Restrepo Mu\u00f1eton","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Cl\u00ednica Noel  Antioquia Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmencita","family":"Padilla","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, Institute of Human Genetics, National Institutes of Health University of the Philippines Manila Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Deleyiannis","sequence":"additional","affiliation":[{"name":"UCHealth Medical Group  Colorado Springs Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaare","family":"Christensen","sequence":"additional","affiliation":[{"name":"Unit of Epidemiology, Department of Public Health University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando A.","family":"Poletta","sequence":"additional","affiliation":[{"name":"CEMIC\u2010CONICET: Center for Medical Education and Clinical Research  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ieda M.","family":"Orioli","sequence":"additional","affiliation":[{"name":"Department of Genetics, Institute of Biology Federal University of Rio de Janeiro  Rio de Janeiro Brazil"},{"name":"Instituto Nacional de Gen\u00e9tica M\u00e9dica Populacional INAGEMP  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline T.","family":"Hecht","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Texas Health Science Center at Houston  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen J.","family":"Bux\u00f3","sequence":"additional","affiliation":[{"name":"Dental and Craniofacial Genomics Core, School of Dental Medicine University of Puerto Rico  San Juan Puerto Rico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azeez","family":"Butali","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, Radiology and Medicine, Iowa Institute for Oral Health Research, College of Dentistry University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wasiu L.","family":"Adeyemo","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Medicine University of Lagos  Lagos Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre R.","family":"Vieira","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of Dental Medicine, Center for Craniofacial and Dental Genetics University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Shaffer","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of Dental Medicine, Center for Craniofacial and Dental Genetics University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Human Genetics, Graduate School of Public Health University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey C.","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth M.","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of Dental Medicine, Center for Craniofacial and Dental Genetics University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Human Genetics, Graduate School of Public Health University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5735-1712","authenticated-orcid":false,"given":"Elizabeth J.","family":"Leslie","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary L.","family":"Marazita","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of Dental Medicine, Center for Craniofacial and Dental Genetics University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Department of Human Genetics, Graduate School of Public Health University of Pittsburgh  Pittsburgh Pennsylvania USA"},{"name":"Clinical and Translational Science Institute, School of Medicine University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.9503.1"},{"key":"e_1_2_8_3_1","volume-title":"Cleft lip and palate: From origin to treatment","author":"Berk N. 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W.","year":"2021","journal-title":"HGG Advances"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22420"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2933"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz567"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.069385"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwi214"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008357"},{"key":"e_1_2_8_17_1","first-page":"531210","article-title":"Variation across 141,456 human exomes and genomes reveals the spectrum of loss\u2010of\u2010function intolerance across human protein\u2010coding genes","author":"Karczewski K. J.","year":"2019","journal-title":"bioRxiv"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1754-7"},{"issue":"13","key":"e_1_2_8_19_1","first-page":"2862","article-title":"A multi\u2010ethnic genome\u2010wide association study identifies novel loci for non\u2010syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13","volume":"25","author":"Leslie E. J.","year":"2016","journal-title":"Human Molecular Genetics"},{"key":"e_1_2_8_20_1","first-page":"207","volume-title":"Comprehensive cleft care","author":"Marazita M. L.","year":"2016"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1159\/000224636"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034517716914"},{"key":"e_1_2_8_23_1","volume-title":"Cleft and craniofacial orthodontics","author":"Moreno Uribe L. 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