{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:58:34Z","timestamp":1790974714868,"version":"4.1.0"},"reference-count":55,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,4,12]],"date-time":"2012-04-12T00:00:00Z","timestamp":1334188800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Human Genetics"],"published-print":{"date-parts":[[2012,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case\u2010control and offspring\u2010parent triad designs into a \u201chybrid design\u201d to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first\u2010trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case\u2010parent triads of isolated clefts and 562 control\u2010parent triads derived from a nationwide study of orofacial clefts in Norway (1996\u20132001). A full maximum\u2010likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway\u2010based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T\u2010box 4 gene (<jats:italic>TBX4<\/jats:italic>) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well\u2010established risk exposures.<\/jats:p>","DOI":"10.1111\/j.1469-1809.2012.00707.x","type":"journal-article","created":{"date-parts":[[2012,4,12]],"date-time":"2012-04-12T17:44:24Z","timestamp":1334252664000},"page":"221-236","source":"Crossref","is-referenced-by-count":25,"title":["Application of a Novel Hybrid Study Design to Explore Gene\u2010Environment Interactions in Orofacial Clefts"],"prefix":"10.1111","volume":"76","author":[{"given":"\u00d8ivind","family":"Skare","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astanand","family":"Jugessur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolv Terje","family":"Lie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen James","family":"Wilcox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey Clark","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Lunde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Truc Trung","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kon Kristian","family":"Gjessing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,4,12]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2003.11.014"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20315"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.580"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.20595"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.333"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20488"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.20049"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(01)06418-2"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwn186"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9416(85)90107-1"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2933"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.22582"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1159\/000119108"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9780511761362"},{"key":"e_1_2_7_16_1","volume-title":"Statistical Methods for Research Workers","author":"Fisher R.","year":"1958"},{"key":"e_1_2_7_17_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1529-8817.2005.00218.x","article-title":"Case\u2010parent triads: Estimating single\u2010 and double\u2010dose effects of fetal and maternal disease gene haplotypes","volume":"70","author":"Gjessing H. 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