{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T18:37:50Z","timestamp":1785263870804,"version":"3.55.0"},"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2011,11,30]],"date-time":"2011-11-30T00:00:00Z","timestamp":1322611200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0028408","type":"journal-article","created":{"date-parts":[[2011,12,1]],"date-time":"2011-12-01T11:35:46Z","timestamp":1322739346000},"page":"e28408","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":27,"title":["A Genetic Signature of Spina Bifida Risk from Pathway-Informed Comprehensive Gene-Variant Analysis"],"prefix":"10.1371","volume":"6","author":[{"given":"Nicholas J.","family":"Marini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J.","family":"Lammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Hardin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Lazaruk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason B.","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis A.","family":"Gilbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Wright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lipzen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Len A.","family":"Pennacchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzan L.","family":"Carmichael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Witte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Rine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2011,11,30]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/ddrr.93","article-title":"Epidemiologic and genetic aspects of spina bifida and other neural tube defects.","volume":"16","author":"KS Au","year":"2010","journal-title":"Dev Disabil Res Rev"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1038\/nrg1181","article-title":"The genetic basis of mammalian neurulation.","volume":"4","author":"AJ Copp","year":"2003","journal-title":"Nat Rev Genet"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/bdra.20552","article-title":"Insights into prevention of human neural tube defects by folic acid arising from consideration of mouse mutants.","volume":"85","author":"MJ Harris","year":"2009","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0306-9877(02)00402-4","article-title":"Diet quality and risk of neural tube defects.","volume":"60","author":"SL Carmichael","year":"2003","journal-title":"Med Hypotheses"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/tera.10060","article-title":"Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States.","volume":"66","author":"LJ Williams","year":"2002","journal-title":"Teratology"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1093\/aje\/153.10.961","article-title":"Neural tube defects in relation to use of folic acid antagonists during pregnancy.","volume":"153","author":"S Hernandez-Diaz","year":"2001","journal-title":"Am J Epidemiol"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/nrn1986","article-title":"Neural tube defects and folate: case far from closed.","volume":"7","author":"HJ Blom","year":"2006","journal-title":"Nat Rev Neurosci"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/bdrc.20100","article-title":"Folate-mediated one-carbon metabolism and neural tube defects: balancing genome synthesis and gene expression.","volume":"81","author":"AE Beaudin","year":"2007","journal-title":"Birth Defects Res C Embryo Today"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1074\/jbc.M808281200","article-title":"Mthfd1 is an essential gene in mice and alters biomarkers of impaired one-carbon metabolism.","volume":"284","author":"AJ MacFarlane","year":"2009","journal-title":"J Biol Chem"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"R113","DOI":"10.1093\/hmg\/ddp347","article-title":"Genetics of human neural tube defects.","volume":"18","author":"ND Greene","year":"2009","journal-title":"Hum Mol Genet"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1002\/ajmg.a.31812","article-title":"Non-Latin European descent could be a requirement for association of NTDs and MTHFR variant 677C > T: a meta-analysis.","volume":"143A","author":"MR Amorim","year":"2007","journal-title":"Am J Med Genet A"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/wsbm.72","article-title":"Gene-environment interactions, folate metabolism and the embryonic nervous system.","volume":"2","author":"ME Ross","year":"2010","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/bdra.20333","article-title":"Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects.","volume":"79","author":"MJ Harris","year":"2007","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"789","DOI":"10.3945\/ajcn.110.002766","article-title":"Shmt1 and de novo thymidylate biosynthesis underlie folate-responsive neural tube defects in mice.","volume":"93","author":"AE Beaudin","year":"2011","journal-title":"Am J Clin Nutr"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00439-008-0616-3","article-title":"Analysis of the MTHFD1 promoter and risk of neural tube defects.","volume":"125","author":"N Carroll","year":"2009","journal-title":"Hum Genet"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/ng0494-357","article-title":"Multifactorial inheritance of neural tube defects: localization of the major gene and recognition of modifiers in ct mutant mice.","volume":"6","author":"PE Neumann","year":"1994","journal-title":"Nat Genet"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.gde.2009.04.010","article-title":"Common vs rare allele hypotheses for complex diseases.","volume":"19","author":"NJ Schork","year":"2009","journal-title":"Curr Opin Genet Dev"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nrg2779","article-title":"Uncovering the roles of rare variants in common disease through whole-genome sequencing.","volume":"11","author":"ET Cirulli","year":"2010","journal-title":"Nat Rev Genet"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"8055","DOI":"10.1073\/pnas.0802813105","article-title":"The prevalence of folate-remedial MTHFR enzyme variants in humans.","volume":"105","author":"NJ Marini","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/bdra.20556","article-title":"An association study of 45 folate-related genes in spina bifida: Involvement of cubilin (CUBN) and tRNA aspartic acid methyltransferase 1 (TRDMT1).","volume":"85","author":"B Franke","year":"2009","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"ref21","first-page":"684","article-title":"Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.","volume":"4","author":"CT Johansen","year":"2011","journal-title":"Nat Genet"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1080\/01621459.1951.10500769","article-title":"The Kolmogorov-Smirnov test for goodness-of-fit.","volume":"46","author":"FJ Massey","year":"1951","journal-title":"J Am Stat Assoc"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1038\/sj.ejhg.5201603","article-title":"Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population.","volume":"14","author":"A Parle-McDermott","year":"2006","journal-title":"Eur J Hum Genet"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1007\/s10038-005-0329-6","article-title":"Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk.","volume":"51","author":"P De Marco","year":"2006","journal-title":"J Hum Genet"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.mrfmmm.2006.09.003","article-title":"A strategy to discover genes that carry multi-allelic or mono-allelic risk for common diseases: a cohort allelic sums test (CAST).","volume":"615","author":"S Morgenthaler","year":"2007","journal-title":"Mutat Res"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"e100038","DOI":"10.1371\/journal.pgen.1000384","article-title":"A groupwise association test for rare mutations using a weighted sum statistic.","volume":"5","author":"BE Madsen","year":"2009","journal-title":"PLoS Genet"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"e13584","DOI":"10.1371\/journal.pone.0013584","article-title":"Comprehensive approach to analyzing rare genetic variants.","volume":"5","author":"TJ Hoffmann","year":"2010","journal-title":"PLoS One"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"55008","DOI":"10.1074\/jbc.M410818200","article-title":"A mathematical model of the folate cycle: new insights into folate homeostasis.","volume":"279","author":"HF Nijhout","year":"2004","journal-title":"J Biol Chem"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jtbi.2003.08.001","article-title":"A mathematical model of the methionine cycle.","volume":"226","author":"MC Reed","year":"2004","journal-title":"J Theor Biol"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1158\/1055-9965.EPI-07-2937","article-title":"Mathematical modeling of folate metabolism: predicted effects of genetic polymorphisms on mechanisms and biomarkers relevant to carcinogenesis.","volume":"17","author":"CM Ulrich","year":"2008","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"4612","DOI":"10.1074\/jbc.M109.079855","article-title":"Mitochondrial C1-tetrahydrofolate synthase (MTHFD1L) supports the flow of mitochondrial one-carbon units into the methyl cycle in embryos.","volume":"285","author":"ST Pike","year":"2010","journal-title":"J Biol Chem"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/bies.20420","article-title":"Mitochondrial one-carbon metabolism is adapted to the specific needs of yeast, plants and mammals.","volume":"28","author":"KE Christensen","year":"2006","journal-title":"Bioessays"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"7597","DOI":"10.1074\/jbc.M409380200","article-title":"Disruption of the mthfd1 gene reveals a monofunctional 10-formyltetrahydrofolate synthetase in mammalian mitochondria.","volume":"280","author":"KE Christensen","year":"2005","journal-title":"J Biol Chem"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"18335","DOI":"10.1074\/jbc.M510623200","article-title":"Regulation of folate-mediated one-carbon metabolism by 10-formyltetrahydrofolate dehydrogenase.","volume":"281","author":"MC Anguera","year":"2006","journal-title":"J Biol Chem"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"38381","DOI":"10.1074\/jbc.M205000200","article-title":"Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses.","volume":"277","author":"K Herbig","year":"2002","journal-title":"J Biol Chem"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0083-6729(08)00402-0","article-title":"Mathematical models of folate-mediated one-carbon metabolism.","volume":"79","author":"HF Nijhout","year":"2008","journal-title":"Vitam Horm"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"17623","DOI":"10.1074\/jbc.M702526200","article-title":"Evidence for small ubiquitin-like modifier-dependent nuclear import of the thymidylate biosynthesis pathway.","volume":"282","author":"CF Woeller","year":"2007","journal-title":"J Biol Chem"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1515\/CCLM.2007.355","article-title":"Small ubiquitin-like modifier-1 (SUMO-1) modification of thymidylate synthase and dihydrofolate reductase.","volume":"45","author":"DD Anderson","year":"2007","journal-title":"Clin Chem Lab Med"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"25846","DOI":"10.1074\/jbc.M802671200","article-title":"Cytoplasmic serine hydroxymethyltransferase regulates the metabolic partitioning of methylenetetrahydrofolate but is not essential in mice.","volume":"283","author":"AJ MacFarlane","year":"2008","journal-title":"J Biol Chem"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1214\/ss\/1056397487","article-title":"Multiple hypothesis testing in microarray experiments.","volume":"18","author":"S Dudoit","year":"2003","journal-title":"Stat Sci"},{"key":"ref41","first-page":"8781","article-title":"Food Standards.","volume":"61","year":"1996","journal-title":"Federal Register"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1016\/0026-0495(94)90004-3","article-title":"Maternal hyperhomocysteinemia: a risk factor for neural-tube defects?","volume":"43","author":"RP Steegers-Theunissen","year":"1994","journal-title":"Metabolism"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0140-6736(95)90165-5","article-title":"Homocysteine metabolism in pregnancies complicated by neural-tube defects.","volume":"345","author":"JL Mills","year":"1995","journal-title":"Lancet"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/humu.20830","article-title":"The MTHFD1 pArg653Gln variant alters enzyme function and increases risk for congenital heart defects.","volume":"30","author":"KE Christensen","year":"2009","journal-title":"Hum Mutat"},{"key":"ref45","first-page":"163","article-title":"Neural tube defects--why are rates high among populations of Mexican descent?","volume":"103","author":"JA Harris","year":"1995","journal-title":"Environ Health Perspect"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1093\/oxfordjournals.aje.a009766","article-title":"Neural tube defects along the Texas-Mexico border, 1993-1995.","volume":"149","author":"KA Hendricks","year":"1999","journal-title":"Am J Epidemiol"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1126\/science.280.5372.2107","article-title":"Embryonic folate metabolism and mouse neural tube defects.","volume":"280","author":"A Fleming","year":"1998","journal-title":"Science"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1002\/humu.21109","article-title":"A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency.","volume":"30","author":"A Parle-McDermott","year":"2009","journal-title":"Hum Mutat"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"5606","DOI":"10.1073\/pnas.062066299","article-title":"A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.","volume":"99","author":"S Friso","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.jnutbio.2004.04.003","article-title":"Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women.","volume":"15","author":"KP Shelnutt","year":"2004","journal-title":"J Nutr Biochem"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1002\/bdra.10040","article-title":"Homocysteine interference in neurulation: a chick embryo model.","volume":"67","author":"LA Afman","year":"2003","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1002\/bdra.20286","article-title":"Integrity of the methylation cycle is essential for mammalian neural tube closure.","volume":"76","author":"LP Dunlevy","year":"2006","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1056\/NEJMoa032909","article-title":"Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.","volume":"351","author":"TM Zucchero","year":"2004","journal-title":"N Engl J Med"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/ajmg.a.30887","article-title":"Variation in IRF6 contributes to nonsyndromic cleft lip and palate.","volume":"137A","author":"SH Blanton","year":"2005","journal-title":"Am J Med Genet A"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"4879","DOI":"10.1093\/hmg\/ddp444","article-title":"FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate.","volume":"18","author":"LM Moreno","year":"2009","journal-title":"Hum Mol Genet"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1093\/aje\/152.11.1017","article-title":"Neural tube defects among Mexican Americans living on the US-Mexico border: effects of folic acid and dietary folate.","volume":"152","author":"L Suarez","year":"2000","journal-title":"Am J Epidemiol"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1097\/00001648-199505000-00005","article-title":"Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects.","volume":"6","author":"GM Shaw","year":"1995","journal-title":"Epidemiology"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"14853","DOI":"10.1073\/pnas.261469998","article-title":"Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase.","volume":"98","author":"K Yamada","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/j.1365-3016.1991.tb00728.x","article-title":"Birth defects monitoring in California: a resource for epidemiological research.","volume":"5","author":"LA Croen","year":"1991","journal-title":"Paediatr Perinat Epidemiol"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1086\/513471","article-title":"Medical sequencing at the extremes of human body mass.","volume":"80","author":"N Ahituv","year":"2007","journal-title":"Am J Hum Genet"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ajhg.2009.01.005","article-title":"A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals.","volume":"84","author":"BL Browning","year":"2009","journal-title":"Am J Hum Genet"},{"issue":"3","key":"ref62","doi-asserted-by":"crossref","DOI":"10.18637\/jss.v021.i03","article-title":"elrm: Software implementing exact-like inference for logistic regression models.","volume":"21","author":"D Zamar","year":"2007","journal-title":"J Stat Softw"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0028408","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T19:15:50Z","timestamp":1540322150000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0028408"}},"subtitle":[],"editor":[{"given":"Osman","family":"El-Maarri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2011,11,30]]},"references-count":62,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2011,11,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0028408","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,11,30]]}}}