{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:40:10Z","timestamp":1790278810832,"version":"4.1.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T00:00:00Z","timestamp":1618531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Two large studies of case\u2013parent trios ascertained through a proband with a non-syndromic orofacial cleft (OFC, which includes cleft lip and palate, cleft lip alone, or cleft palate alone) were used to test for possible gene\u2013environment (G \u00d7 E) interaction between genome-wide markers (both observed and imputed) and self-reported maternal exposure to smoking, alcohol consumption, and multivitamin supplementation during pregnancy. The parent studies were as follows: GENEVA, which included 1,939 case\u2013parent trios recruited largely through treatment centers in Europe, the United States, and Asia, and 1,443 case\u2013parent trios from the Pittsburgh Orofacial Cleft Study (POFC) also ascertained through a proband with an OFC including three major racial\/ethnic groups (European, Asian, and Latin American). Exposure rates to these environmental risk factors (maternal smoking, alcohol consumption, and multivitamin supplementation) varied across studies and among racial\/ethnic groups, creating substantial differences in power to detect G \u00d7 E interaction, but the trio design should minimize spurious results due to population stratification. The GENEVA and POFC studies were analyzed separately, and a meta-analysis was conducted across both studies to test for G \u00d7 E interaction using the 2 df test of gene and G \u00d7 E interaction and the 1 df test for G \u00d7 E interaction alone. The 2 df test confirmed effects for several recognized risk genes, suggesting modest G \u00d7 E effects. This analysis did reveal suggestive evidence for G \u00d7 Vitamin interaction for <jats:italic>CASP9<\/jats:italic> on 1p36 located about 3 Mb from <jats:italic>PAX7<\/jats:italic>, a recognized risk gene. Several regions gave suggestive evidence of G \u00d7 E interaction in the 1 df test. For example, for G \u00d7 Smoking interaction, the 1 df test suggested markers in <jats:italic>MUSK<\/jats:italic> on 9q31.3 from meta-analysis. Markers near <jats:italic>SLCO3A1<\/jats:italic> also showed suggestive evidence in the 1 df test for G \u00d7 Alcohol interaction, and rs41117 near <jats:italic>RETREG1<\/jats:italic> (a.k.a. <jats:italic>FAM134B<\/jats:italic>) also gave suggestive significance in the meta-analysis of the 1 df test for G \u00d7 Vitamin interaction. While it remains quite difficult to obtain definitive evidence for G \u00d7 E interaction in genome-wide studies, perhaps due to small effect sizes of individual genes combined with low exposure rates, this analysis of two large case\u2013parent trio studies argues for considering possible G \u00d7 E interaction in any comprehensive study of complex and heterogeneous disorders such as OFC.<\/jats:p>","DOI":"10.3389\/fcell.2021.621018","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T18:28:08Z","timestamp":1618597688000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Detecting Gene-Environment Interaction for Maternal Exposures Using Case-Parent Trios Ascertained Through a Case With Non-Syndromic Orofacial Cleft"],"prefix":"10.3389","volume":"9","author":[{"given":"Wanying","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sowmya","family":"Venkataraghavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline B.","family":"Hetmanski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J.","family":"Leslie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary L.","family":"Marazita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Feingold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth M.","family":"Weinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Ruczinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Taub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan F.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debashree","family":"Ray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri H.","family":"Beaty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1002\/gepi.21989","article-title":"A perspective on interaction effects in genetic association studies.","volume":"40","author":"Aschard","year":"2016","journal-title":"Genet. 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