Open Access Highly Accessed Research article

Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

Faith Pangilinan1, Anne M Molloy2, James L Mills3, James F Troendle4, Anne Parle-McDermott5, Caroline Signore6, Valerie B O’Leary7, Peter Chines8, Jessica M Seay1, Kerry Geiler-Samerotte1, Adam Mitchell1, Julia E VanderMeer1, Kristine M Krebs1, Angelica Sanchez1, Joshua Cornman-Homonoff1, Nicole Stone1, Mary Conley3, Peadar N Kirke9, Barry Shane10, John M Scott11 and Lawrence C Brody112*

Author affiliations

1 Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

2 Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland

3 Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA

4 Department of Health and Human Services, Office of Biostatistics Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

5 School of Biotechnology, Dublin City University, Dublin, Ireland

6 Department of Health and Human Services, Pregnancy and Perinatology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

7 International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland

8 Department of Health and Human Services, Molecular Genetics Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

9 Child Health Epidemiology Unit, Health Research Board, Dublin, Ireland

10 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, 94720-3104, USA

11 School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland

12 Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, Building 50, Room 5306, 50 South Drive, MSC 8004, Bethesda, MD, 20892-8004, USA

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Citation and License

BMC Medical Genetics 2012, 13:62  doi:10.1186/1471-2350-13-62

Published: 2 August 2012

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.

Keywords:
Neural tube defects; Spina bifida; Folic acid; One-carbon metabolism; Candidate gene