{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:30:36Z","timestamp":1768566636645,"version":"3.49.0"},"posted":{"date-parts":[[2024,12,17]]},"group-title":"Genetic and Genomic Medicine","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T00:00:00Z","timestamp":1734393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,12,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Maternal exposures are known to influence the risk of isolated cleft lip with or without cleft palate (CL\/P) \u2013 a common and highly heritable birth defect with a multifactorial etiology. To identify new CL\/P risk loci, we conducted a genome-wide gene-environment interaction (GEI) analysis of CL\/P on a sample of 540 cases and 260 controls recruited from the Philippines, incorporating the interaction effects of genetic variants with maternal smoking and vitamin use. As GEI analyses are typically low in power and the results can be difficult to interpret, we used multiple testing frameworks to evaluate potential GEI effects: 1 degree-of-freedom (1df) GxE test, the 3df joint test, and the two-step EDGE approach. While we did not detect any genome-wide significant interactions, we detected 12 suggestive GEI with smoking and 25 suggestive GEI with vitamin use between all testing frameworks. Several of these loci showed biological plausibility. Notable interactions with smoking include loci near\n                  <jats:italic>FEZF1<\/jats:italic>\n                  ,\n                  <jats:italic>TWIST2,<\/jats:italic>\n                  and\n                  <jats:italic>NET1.<\/jats:italic>\n                  While\n                  <jats:italic>FEZF1<\/jats:italic>\n                  is involved in early neuronal development,\n                  <jats:italic>TWIST2<\/jats:italic>\n                  and\n                  <jats:italic>NET1<\/jats:italic>\n                  regulate epithelial-mesenchymal transition which is required for proper lip and palate fusion. Interactions with vitamins encompass\n                  <jats:italic>CECR2<\/jats:italic>\n                  \u2014 a chromatin remodeling protein required for neural tube closure\u2014and\n                  <jats:italic>FURIN,<\/jats:italic>\n                  a critical protease during early embryogenesis that activates various growth factor and extracellular-matrix protein. The activity of both proteins is influenced by folic acid. Our findings highlight the critical role of maternal exposures in identifying genes associated with structural birth defects such as CL\/P and provide new paths to explore for CL\/P genetics.\n                <\/jats:p>","DOI":"10.1101\/2024.12.16.24319123","type":"posted-content","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T08:40:45Z","timestamp":1734684045000},"source":"Crossref","is-referenced-by-count":0,"title":["Gene-by-environment interactions involving maternal exposures with orofacial cleft risk in Filipinos"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5349-6562","authenticated-orcid":false,"given":"Zeynep","family":"Erdogan-Yildirim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5483-0833","authenticated-orcid":false,"given":"Jenna C.","family":"Carlson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7117-9536","authenticated-orcid":false,"given":"Nandita","family":"Mukhopadhyay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5735-1712","authenticated-orcid":false,"given":"Elizabeth J.","family":"Leslie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5812-1871","authenticated-orcid":false,"given":"Carmencita","family":"Padilla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-6551","authenticated-orcid":false,"given":"Jeffrey C.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7644-1705","authenticated-orcid":false,"given":"Terri H.","family":"Beaty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9467-4556","authenticated-orcid":false,"given":"Seth M.","family":"Weinberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2648-2832","authenticated-orcid":false,"given":"Mary L.","family":"Marazita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1897-1131","authenticated-orcid":false,"given":"John R.","family":"Shaffer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024122006302023000_2024.12.16.24319123v1.1","doi-asserted-by":"publisher","DOI":"10.1597\/1545-1569(1997)034<0007:CAESOC>2.3.CO;2"},{"key":"2024122006302023000_2024.12.16.24319123v1.2","first-page":"27","article-title":"Profile of Oral Cleft Cases Reported in the Philippine Oral Cleft Registry from May 2003 to December 2006","volume":"42","author":"Paz, E.M.C.C. la","year":"2008","journal-title":"Acta Med Philipp"},{"key":"2024122006302023000_2024.12.16.24319123v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2005.03.003"},{"key":"2024122006302023000_2024.12.16.24319123v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20179"},{"key":"2024122006302023000_2024.12.16.24319123v1.5","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/bdra.20348","article-title":"Maternal plasma pyridoxal-5\u2019-phosphate concentrations and risk of isolated oral clefts in the Philippines","volume":"79","year":"2007","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"2024122006302023000_2024.12.16.24319123v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20037"},{"key":"2024122006302023000_2024.12.16.24319123v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.23417"},{"key":"2024122006302023000_2024.12.16.24319123v1.8","doi-asserted-by":"crossref","unstructured":"Jafari, A. , Rajabi, A. , Gholian-Aval, M. , Peyman, N. , Mahdizadeh, M. , and Tehrani, H . 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