{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T19:52:29Z","timestamp":1780429949807,"version":"3.54.1"},"reference-count":56,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R03DE026208, R01DE026767, R03DE026509, R03DE028340"],"award-info":[{"award-number":["R03DE026208, R01DE026767, R03DE026509, R03DE028340"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R03HD098552"],"award-info":[{"award-number":["R03HD098552"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Orofacial cleft (OFC) is one of the most prevalent birth defects, leading to substantial and long-term burdens in a newborn\u2019s quality of life. Although studies revealed several genetic variants associated with the birth defect, novel approaches may provide additional clues about its etiology. Using the Center for Craniofacial and Dental Genetics project data (n = 10,542), we performed linear mixed-model analyses to study the genetic compositions of OFC and investigated the dependence among identified loci using conditional analyses. To identify genes associated with OFC, we conducted a transcriptome-wide association study (TWAS) based on predicted expression levels. In addition to confirming the previous findings at four loci, 1q32.2, 8q24, 2p24.2 and 17p13.1, we untwined two independent loci at 1q32.2, TRAF3IP3 and IRF6. The sentinel SNP in TRAF3IP3 (rs2235370, p-value = 5.15 \u00d7 10\u22129) was independent of the sentinel SNP at IRF6 (rs2235373, r2 &lt; 0.3). We found that the IRF6 effect became nonsignificant once the 8q24 effect was conditioned, while the TRAF3IP3 effect remained significant. Furthermore, we identified nine genes associated with OFC in TWAS, implicating a glutathione synthesis and drug detoxification pathway. We identified some meaningful additions to the OFC etiology using novel statistical methods in the existing data.<\/jats:p>","DOI":"10.3390\/genes11111280","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T21:21:00Z","timestamp":1604006460000},"page":"1280","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Secondary Genome-Wide Association Study Using Novel Analytical Strategies Disentangle Genetic Components of Cleft Lip and\/or Cleft Palate in 1q32.2"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9747-8363","authenticated-orcid":false,"given":"Yunju","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Epidemiology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3163-8093","authenticated-orcid":false,"given":"Akiko","family":"Suzuki","sequence":"additional","affiliation":[{"name":"School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3975-6836","authenticated-orcid":false,"given":"Junichi","family":"Iwata","sequence":"additional","affiliation":[{"name":"School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goo","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R73","DOI":"10.1093\/hmg\/ddh052","article-title":"Genetics of cleft lip and palate: Syndromic genes contribute to the incidence of non-syndromic clefts","volume":"13","author":"Stanier","year":"2004","journal-title":"Hum. 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