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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2012

Open Access 01-12-2012 | Research article

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

Authors: Faith Pangilinan, Anne M Molloy, James L Mills, James F Troendle, Anne Parle-McDermott, Caroline Signore, Valerie B O’Leary, Peter Chines, Jessica M Seay, Kerry Geiler-Samerotte, Adam Mitchell, Julia E VanderMeer, Kristine M Krebs, Angelica Sanchez, Joshua Cornman-Homonoff, Nicole Stone, Mary Conley, Peadar N Kirke, Barry Shane, John M Scott, Lawrence C Brody

Published in: BMC Medical Genetics | Issue 1/2012

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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.
Appendix
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Metadata
Title
Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects
Authors
Faith Pangilinan
Anne M Molloy
James L Mills
James F Troendle
Anne Parle-McDermott
Caroline Signore
Valerie B O’Leary
Peter Chines
Jessica M Seay
Kerry Geiler-Samerotte
Adam Mitchell
Julia E VanderMeer
Kristine M Krebs
Angelica Sanchez
Joshua Cornman-Homonoff
Nicole Stone
Mary Conley
Peadar N Kirke
Barry Shane
John M Scott
Lawrence C Brody
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2012
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-13-62

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