title: Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects.
abstract: BACKGROUND
  Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.
  
  
  METHODS
  A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case-control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.
  
  
  RESULTS
  Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003-0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.
  
  
  CONCLUSIONS
  To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.
authors.affiliation: Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Faith
authors.initials: F
authors.lastname: Pangilinan
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.forename: James F
authors.initials: JF
authors.lastname: Troendle
authors.forename: Anne
authors.initials: A
authors.lastname: Parle-McDermott
authors.forename: Caroline
authors.initials: C
authors.lastname: Signore
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Leary
authors.forename: Peter
authors.initials: P
authors.lastname: Chines
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Seay
authors.forename: Kerry
authors.initials: K
authors.lastname: Geiler-Samerotte
authors.forename: Adam
authors.initials: A
authors.lastname: Mitchell
authors.forename: Julia E
authors.initials: JE
authors.lastname: VanderMeer
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Krebs
authors.forename: Angelica
authors.initials: A
authors.lastname: Sanchez
authors.forename: Joshua
authors.initials: J
authors.lastname: Cornman-Homonoff
authors.forename: Nicole
authors.initials: N
authors.lastname: Stone
authors.forename: Mary
authors.initials: M
authors.lastname: Conley
authors.forename: Peadar N
authors.initials: PN
authors.lastname: Kirke
authors.forename: Barry
authors.initials: B
authors.lastname: Shane
authors.forename: John M
authors.initials: JM
authors.lastname: Scott
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007494:Ireland; D051379:Mice; D009436:Neural Tube Defects / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014805:Vitamin B 12 / Q000235:genetics / Q000378:metabolism
chemical_list: D005492:Folic Acid; D014805:Vitamin B 12