{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:48:42Z","timestamp":1760057322887,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:00:00Z","timestamp":1738627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research (CIHR)","doi-asserted-by":"publisher","award":["PJT-148911"],"award-info":[{"award-number":["PJT-148911"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: We investigated maternal and parent-of-origin (PoO) gene-environment interaction effects on the risk of nonsyndromic orofacial clefts for two maternal environmental factors: periconceptional smoking and folic acid supplementation. Methods: Genome-wide single nucleotide polymorphisms (SNPs) genotypes and TopMed-imputed genotypes were obtained for case-parent triads from the EUROCRAN and ITALCLEFT studies. Candidate regions were selected around target SNPs from a previous genome-wide association study, resulting in 12 (726 SNPs) and 11 regions (730 SNPs) for maternal and PoO effects, respectively. Log-linear models were used to analyze 404 case-parent triads and 40 case-parent dyads. p-values were combined across regions. Results: None of the interactions reached statistical significance after correction for the number of regions tested. Nominally significant (pooled p-values &lt; 0.05) interactions pointed to regions in or close to genes LRRC7 (maternal gene-folate interaction), NCKAP5 (PoO-smoking interaction), and IFT43 and GPATCH2L (PoO-folate interaction). Conclusions: Our results suggested that the genetic effects in or around these genes were heightened under periconceptional exposure to tobacco or no folic acid supplementation. The involvement of these genes in orofacial cleft development, in conjunction with environmental exposures, should be further studied.<\/jats:p>","DOI":"10.3390\/genes16020195","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T05:55:22Z","timestamp":1738648522000},"page":"195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Maternal and Parent-of-Origin Gene\u2013Environment Effects on the Etiology of Orofacial Clefting"],"prefix":"10.3390","volume":"16","author":[{"given":"Nikola","family":"Rasevic","sequence":"first","affiliation":[{"name":"School of Epidemiology and Public Health, University of Ottawa, 600 Peter Morand Crescent, Ottawa, ON K1G 5Z3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Bastasic","sequence":"additional","affiliation":[{"name":"School of Epidemiology and Public Health, University of Ottawa, 600 Peter Morand Crescent, Ottawa, ON K1G 5Z3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1448-9516","authenticated-orcid":false,"given":"Michele","family":"Rubini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Rehabilitation, University of Ferrara, Via Ludovico Ariosto 35, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohan R.","family":"Rakesh","sequence":"additional","affiliation":[{"name":"School of Epidemiology and Public Health, University of Ottawa, 600 Peter Morand Crescent, Ottawa, ON K1G 5Z3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly M.","family":"Burkett","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, University of Ottawa, 150 Louis Pasteur Private, Ottawa, ON K1N 6N5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debashree","family":"Ray","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205, USA"},{"name":"Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter A.","family":"Mossey","sequence":"additional","affiliation":[{"name":"World Health Organization\u2013Collaborating Centre for Oral and Craniofacial Research, Dental Hospital and School, University of Dundee, Nethergate, Dundee DD1 4HN, Scotland, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7824-4978","authenticated-orcid":false,"given":"Borut","family":"Peterlin","sequence":"additional","affiliation":[{"name":"Clinical Institute of Genomic Medicine, University Medical Center, Zalo\u0161ka cesta 7, 1000 Ljubljana, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Faisal J.","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Rehabilitation, University of Ferrara, Via Ludovico Ariosto 35, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9050-1030","authenticated-orcid":false,"given":"Amin","family":"Ravaei","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Rehabilitation, University of Ferrara, Via Ludovico Ariosto 35, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Autelitano","sequence":"additional","affiliation":[{"name":"Smile House Milan, Regional Centre for Orofacial Clefts and Craniofacial Anomalies, Department of Cranio-Maxillo-Facial Surgery, San Paolo Hospital, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9596-570X","authenticated-orcid":false,"given":"Maria C.","family":"Meazzini","sequence":"additional","affiliation":[{"name":"Smile House Milan, Regional Centre for Orofacial Clefts and Craniofacial Anomalies, Department of Cranio-Maxillo-Facial Surgery, San Paolo Hospital, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5026-5531","authenticated-orcid":false,"given":"Julian","family":"Little","sequence":"additional","affiliation":[{"name":"School of Epidemiology and Public Health, University of Ottawa, 600 Peter Morand Crescent, Ottawa, ON K1G 5Z3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8747-0846","authenticated-orcid":false,"given":"Marie-H\u00e9l\u00e8ne","family":"Roy-Gagnon","sequence":"additional","affiliation":[{"name":"School of Epidemiology and Public Health, University of Ottawa, 600 Peter Morand Crescent, Ottawa, ON K1G 5Z3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1002\/dvdy.20646","article-title":"Development of the upper lip: Morphogenetic and molecular mechanisms","volume":"235","author":"Jiang","year":"2006","journal-title":"Dev. Dyn."},{"key":"ref_2","first-page":"S11","article-title":"Global Birth Prevalence of Orofacial Clefts: A Systematic Review","volume":"98","author":"Panamonta","year":"2015","journal-title":"J. Med. Assoc. Thai"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1136\/bmj.38106.559120.7C","article-title":"Long term follow up study of survival associated with cleft lip and palate at birth","volume":"328","author":"Christensen","year":"2004","journal-title":"BMJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1080\/14767050500072854","article-title":"Are isolated facial cleft lip and palate associated with increased perinatal mortality? A cohort study from the West Midlands Region, 1995\u20131997","volume":"17","author":"Ngai","year":"2005","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1136\/bmj.39458.563611.AE","article-title":"Familial risk of oral clefts by morphological type and severity: Population based cohort study of first degree relatives","volume":"336","author":"Sivertsen","year":"2008","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1098\/rstb.2008.0238","article-title":"What are maternal effects (and what are they not)?","volume":"364","author":"Wolf","year":"2009","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/nrg3543","article-title":"Genomic imprinting and parent-of-origin effects on complex traits","volume":"14","author":"Lawson","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/ajmg.a.35257","article-title":"Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts","volume":"158A","author":"Shi","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Jugessur, A., Shi, M., Gjessing, H.K., Lie, R.T., Wilcox, A.J., Weinberg, C.R., Christensen, K., Boyles, A.L., Daack-Hirsch, S., and Nguyen, T.T. (2010). Maternal genes and facial clefts in offspring: A comprehensive search for genetic associations in two population-based cleft studies from Scandinavia. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011493"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/ejhg.2013.235","article-title":"Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts","volume":"22","author":"Garg","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1002\/bdr2.1827","article-title":"Folate intake, markers of folate status and oral clefts: An updated set of systematic reviews and meta-analyses","volume":"112","author":"Zhou","year":"2020","journal-title":"Birth Defects Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1097\/EDE.0b013e3181690731","article-title":"Maternal smoking and oral clefts: The role of detoxification pathway genes","volume":"19","author":"Lie","year":"2008","journal-title":"Epidemiology"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sabbagh, H.J., Hassan, M.H., Innes, N.P., Elkodary, H.M., Little, J., and Mossey, P.A. (2015). Passive smoking in the etiology of non-syndromic orofacial clefts: A systematic review and meta-analysis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116963"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1597\/16-037","article-title":"Genetic Interactions in Nonsyndromic Orofacial Clefts in Europe-EUROCRAN Study","volume":"54","author":"Mossey","year":"2017","journal-title":"Cleft Palate Craniofac. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1111\/j.1529-8817.2005.00218.x","article-title":"Case-parent triads: Estimating single- and double-dose effects of fetal and maternal disease gene haplotypes","volume":"70","author":"Gjessing","year":"2006","journal-title":"Ann. Hum. Genet."},{"key":"ref_16","unstructured":"R Core Team (2021). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1038\/s41588-020-0676-4","article-title":"Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale","volume":"52","author":"Li","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"The GTEx Consortium (2020). The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science, 369, 1318\u20131330.","DOI":"10.1126\/science.aaz1776"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D896","DOI":"10.1093\/nar\/gkw1133","article-title":"The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog)","volume":"45","author":"MacArthur","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lin, L., Du, Y., Niu, G., Xia, S., and Liu, J. (2023). Folate deficiency may increase the risk for elevated TSH in patients with type 2 diabetes mellitus. BMC Endocr. Disord., 23.","DOI":"10.1186\/s12902-023-01422-2"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gene Ontology Consortium, Aleksander, S.A., Balhoff, J., Carbon, S., Cherry, J.M., Drabkin, H.J., Ebert, D., Feuermann, M., Gaudet, P., and Harris, N.L. (2023). The Gene Ontology knowledgebase in 2023. Genetics, 224, iyad031.","DOI":"10.1093\/genetics\/iyad031"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.gde.2005.03.003","article-title":"Orofacial clefting: Recent insights into a complex trait","volume":"15","author":"Jugessur","year":"2005","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.0009-9163.2004.00225.x","article-title":"Taking it to the max: The genetic and developmental mechanisms coordinating midfacial morphogenesis and dysmorphology","volume":"65","author":"Cox","year":"2004","journal-title":"Clin. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1096\/fj.02-0967fje","article-title":"Genomic and transcriptional alterations in mouse fetus liver after transplacental exposure to cigarette smoke","volume":"17","author":"Izzotti","year":"2003","journal-title":"FASEB J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12967-015-0384-5","article-title":"DNA methylation patterns in newborns exposed to tobacco in utero","volume":"13","author":"Ivorra","year":"2015","journal-title":"J. Transl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1002\/bdr2.1768","article-title":"Cellular and developmental basis of orofacial clefts","volume":"112","author":"Ji","year":"2020","journal-title":"Birth Defects Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/ahg.12224","article-title":"Parent-of-origin-environment interactions in case-parent triads with or without independent controls","volume":"82","author":"Gjerdevik","year":"2018","journal-title":"Ann. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Haaland, O.A., Jugessur, A., Gjerdevik, M., Romanowska, J., Shi, M., Beaty, T.H., Marazita, M.L., Murray, J.C., Wilcox, A.J., and Lie, R.T. (2017). Genome-wide analysis of parent-of-origin interaction effects with environmental exposure (PoOxE): An application to European and Asian cleft palate trios. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184358"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Haaland, O.A., Lie, R.T., Romanowska, J., Gjerdevik, M., Gjessing, H.K., and Jugessur, A. (2018). A Genome-Wide Search for Gene-Environment Effects in Isolated Cleft Lip with or without Cleft Palate Triads Points to an Interaction between Maternal Periconceptional Vitamin Use and Variants in ESRRG. Front. Genet., 9.","DOI":"10.3389\/fgene.2018.00060"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhang, W., Venkataraghavan, S., Hetmanski, J.B., Leslie, E.J., Marazita, M.L., Feingold, E., Weinberg, S.M., Ruczinski, I., Taub, M.A., and Scott, A.F. (2021). Detecting Gene-Environment Interaction for Maternal Exposures Using Case-Parent Trios Ascertained Through a Case with Non-Syndromic Orofacial Cleft. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.621018"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/bdra.22885","article-title":"Evidence of gene-environment interaction for the RUNX2 gene and environmental tobacco smoke in controlling the risk of cleft lip with\/without cleft palate","volume":"94","author":"Wu","year":"2012","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/gepi.22453","article-title":"Benchmarking statistical methods for analyzing parent-child dyads in genetic association studies","volume":"46","author":"Ray","year":"2022","journal-title":"Genet. Epidemiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Little, J., Higgins, J.P., Ioannidis, J.P., Moher, D., Gagnon, F., von Elm, E., Khoury, M.J., Cohen, B., Davey-Smith, G., and Grimshaw, J. (2009). STrengthening the REporting of Genetic Association Studies (STREGA): An extension of the STROBE statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000022"},{"key":"ref_35","unstructured":"Rasevic, N. (2021). Maternal and Parent-of-Origin Effects on the Etiology of Orofacial Clefting. [Master\u2019s Thesis, University of Ottawa]."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/2\/195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:26:34Z","timestamp":1760027194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/2\/195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,4]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["genes16020195"],"URL":"https:\/\/doi.org\/10.3390\/genes16020195","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2025,2,4]]}}}