title: Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects.
abstract: BACKGROUND
  Neural tube defects (NTDs), which are among the most common congenital malformations, are influenced by environmental and genetic factors. Low maternal folate is the strongest known contributing factor, making variants in genes in the folate metabolic pathway attractive candidates for NTD risk. Multiple studies have identified nominally significant allelic associations with NTDs. We tested whether associations detected in a large Irish cohort could be replicated in an independent population.
  
  
  METHODS
  Replication tests of 24 nominally significant NTD associations were performed in racially/ethnically matched populations. Family-based tests of fifteen nominally significant single nucleotide polymorphisms (SNPs) were repeated in a cohort of NTD trios (530 cases and their parents) from the United Kingdom, and case-control tests of nine nominally significant SNPs were repeated in a cohort (190 cases, 941 controls) from New York State (NYS). Secondary hypotheses involved evaluating the latter set of nine SNPs for NTD association using alternate case-control models and NTD groupings in white, African American and Hispanic cohorts from NYS.
  
  
  RESULTS
  Of the 24 SNPs tested for replication, ADA rs452159 and MTR rs10925260 were significantly associated with isolated NTDs. Of the secondary tests performed, ARID1A rs11247593 was associated with NTDs in whites, and ALDH1A2 rs7169289 was associated with isolated NTDs in African Americans.
  
  
  CONCLUSIONS
  We report a number of associations between SNP genotypes and neural tube defects. These associations were nominally significant before correction for multiple hypothesis testing. These corrections are highly conservative for association studies of untested hypotheses, and may be too conservative for replication studies. We therefore believe the true effect of these four nominally significant SNPs on NTD risk will be more definitively determined by further study in other populations, and eventual meta-analysis.
authors.affiliation: Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Room 5306, 50 South Drive, Bethesda, MD, 20892-8004, USA. faith@mail.nih.gov.
authors.forename: Faith
authors.initials: F
authors.lastname: Pangilinan
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland. amolloy@tcd.ie.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.affiliation: Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. millsj@exchange.nih.gov.
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.affiliation: Office of Biostatistics Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. troendlj@nhlbi.nih.gov.
authors.forename: James F
authors.initials: JF
authors.lastname: Troendle
authors.affiliation: School of Biotechnology, Dublin City University, Dublin, Ireland. anne.parle-mcdermott@dcu.ie.
authors.forename: Anne
authors.initials: A
authors.lastname: Parle-McDermott
authors.affiliation: New York State Department of Health, Division of Genetics, Wadsworth Center, Albany, NY, 12201, USA. dmk11@health.state.ny.us.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Kay
authors.affiliation: New York State Department of Health, Congenital Malformations Registry, Troy, NY, 12180, USA. mlb10@health.state.ny.us.|Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, NY, 12144, USA. mlb10@health.state.ny.us.
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Browne
authors.affiliation: New York State Department of Health, Division of Genetics, Wadsworth Center, Albany, NY, 12201, USA. exc14@health.state.ny.us.
authors.forename: Emily C
authors.initials: EC
authors.lastname: McGrath
authors.affiliation: Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Room 5306, 50 South Drive, Bethesda, MD, 20892-8004, USA. habaan@mail.nih.gov.
authors.forename: Hatice Ozel
authors.initials: HO
authors.lastname: Abaan
authors.affiliation: Evidence Centre, Health Research Board, Dublin, Ireland. msutton@hrb.ie.
authors.forename: Marie
authors.initials: M
authors.lastname: Sutton
authors.affiliation: Child Health Epidemiology Unit, Health Research Board, Dublin, Ireland. pkirke@live.ie.
authors.forename: Peadar N
authors.initials: PN
authors.lastname: Kirke
authors.affiliation: New York State Department of Health, Division of Genetics, Wadsworth Center, Albany, NY, 12201, USA. caggana@wadsworth.org.
authors.forename: Michele
authors.initials: M
authors.lastname: Caggana
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, 94720-3104, USA. bandie@berkeley.edu.
authors.forename: Barry
authors.initials: B
authors.lastname: Shane
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland. lbrody@mail.nih.gov.
authors.forename: John M
authors.initials: JM
authors.lastname: Scott
authors.affiliation: Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Room 5306, 50 South Drive, Bethesda, MD, 20892-8004, USA. lbrody@mail.nih.gov.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000243:Adenosine Deaminase / Q000235:genetics*; D001741:Black or African American / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D044466:Asian People / Q000235:genetics; D004268:DNA-Binding Proteins; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D009436:Neural Tube Defects / Q000208:ethnology* / Q000235:genetics*; D009518:New York / Q000208:ethnology; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D050697:Retinal Dehydrogenase / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D006113:United Kingdom / Q000208:ethnology; D044465:White People / Q000235:genetics
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C585801:MTR protein, human; C548482:ADA protein, human; D000243:Adenosine Deaminase