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Open Access 01-12-2014 | Research article

Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects

Authors: Faith Pangilinan, Anne M Molloy, James L Mills, James F Troendle, Anne Parle-McDermott, Denise M Kay, Marilyn L Browne, Emily C McGrath, Hatice Ozel Abaan, Marie Sutton, Peadar N Kirke, Michele Caggana, Barry Shane, John M Scott, Lawrence C Brody

Published in: BMC Medical Genetics | Issue 1/2014

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.

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Title: Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects
Authors: Faith Pangilinan
Anne M Molloy
James L Mills
James F Troendle
Anne Parle-McDermott
Denise M Kay
Marilyn L Browne
Emily C McGrath
Hatice Ozel Abaan
Marie Sutton
Peadar N Kirke
Michele Caggana
Barry Shane
John M Scott
Lawrence C Brody
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2014
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-014-0102-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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