title: Profiling placental and fetal DNA methylation in human neural tube defects.
abstract: BACKGROUND
  The incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program. Despite the fact that few Canadians currently exhibit folate deficiency, NTDs are still the second most common congenital abnormality. FA fortification may have aided in reducing the incidence of NTDs by overcoming abnormal one carbon metabolism cycling, the process which provides one carbon units for methylation of DNA. We considered that NTDs persisting in a folate-replete population may also occur in the context of FA-independent compromised one carbon metabolism, and that this might manifest as abnormal DNA methylation (DNAm). Second trimester human placental chorionic villi, kidney, spinal cord, brain, and muscle were collected from 19 control, 22 spina bifida, and 15 anencephalic fetuses in British Columbia, Canada. DNA was extracted, assessed for methylenetetrahydrofolate reductase (MTHFR) genotype and for genome-wide DNAm using repetitive elements, in addition to the Illumina Infinium HumanMethylation450 (450k) array.
  
  
  RESULTS
  No difference in repetitive element DNAm was noted between NTD status groups. Using a false discovery rate <0.05 and average group difference in DNAm ≥0.05, differentially methylated array sites were identified only in (1) the comparison of anencephaly to controls in chorionic villi (n = 4 sites) and (2) the comparison of spina bifida to controls in kidney (n = 3342 sites).
  
  
  CONCLUSIONS
  We suggest that the distinctive DNAm of spina bifida kidneys may be consequent to the neural tube defect or reflective of a common etiology for abnormal neural tube and renal development. Though there were some small shifts in DNAm in the other tested tissues, our data do not support the long-standing hypothesis of generalized altered genome-wide DNAm in NTDs. This finding may be related to the fact that most Canadians are not folate deficient, but it importantly opens the field to the investigation of other epigenetic and non-epigenetic mechanisms in the etiology of NTDs.
authors.affiliation: Child and Family Research Institute, 950 W 28th Ave, Vancouver, BC V5Z 4H4 UK ; Dept of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC V6H 3N1 UK ; Dept of Obstetrics and Gynaecology, University of British Columbia, C420-4500 Oak St, Vancouver, BC V6H 3N1 UK.
authors.forename: E Magda
authors.initials: EM
authors.lastname: Price
authors.affiliation: Child and Family Research Institute, 950 W 28th Ave, Vancouver, BC V5Z 4H4 UK ; Dept of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC V6H 3N1 UK.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Peñaherrera
authors.affiliation: Child and Family Research Institute, 950 W 28th Ave, Vancouver, BC V5Z 4H4 UK.
authors.forename: Elodie
authors.initials: E
authors.lastname: Portales-Casamar
authors.affiliation: Centre for High-Throughput Biology, University of British Columbia, 2185 East Mall, Vancouver, V6T 1Z4 UK ; Dept of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1 UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Pavlidis
authors.affiliation: Dept of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC V6H 3N1 UK.
authors.forename: Margot I
authors.initials: MI
authors.lastname: Van Allen
authors.affiliation: Dept of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC V6H 3N1 UK ; Dept of Pathology and Laboratory Medicine, Rm G227-2211, Wesbrook Mall, Vancouver, BC V6T 2B5 UK.
authors.forename: Deborah E
authors.initials: DE
authors.lastname: McFadden
authors.affiliation: Child and Family Research Institute, 950 W 28th Ave, Vancouver, BC V5Z 4H4 UK ; Dept of Medical Genetics, University of British Columbia, C201-4500 Oak St, Vancouver, BC V6H 3N1 UK.
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
keywords: 450k array; Anencephaly; DNA methylation (DNAm); Epigenome-wide association study (EWAS); Illumina HumanMethylation450 BeadChip; Neural tube defects (NTDs); Spina bifida