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

BMC Medical Genetics

Lawrence C Brody⁷  John M Scott⁴  Barry Shane¹  Michele Caggana³  Peadar N Kirke⁹  Marie Sutton^1,11  Hatice Ozel Abaan⁷  Emily C McGrath³  Marilyn L Browne⁵  Denise M Kay³  Anne Parle-McDermott²  James F Troendle^1,10  James L Mills⁸  Anne M Molloy⁶  Faith Pangilinan⁷ 

[1] Department of Nutritional Sciences and Toxicology, University of California, Berkeley 94720-3104, CA, USA;School of Biotechnology, Dublin City University, Dublin, Ireland;New York State Department of Health, Division of Genetics, Wadsworth Center, Albany 12201, NY, USA;School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland;Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer 12144, NY, USA;Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland;Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Room 5306, 50 South Drive, Bethesda 20892-8004, MD, USA;Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA;Child Health Epidemiology Unit, Health Research Board, Dublin, Ireland;Office of Biostatistics Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA;Evidence Centre, Health Research Board, Dublin, Ireland

关键词: Replication;    One-carbon metabolism;    Folic acid;    Folate;    Spina bifida;    Neural tube defects;   

Others  :  1090499
DOI  :  10.1186/s12881-014-0102-9

 received in 2014-03-12, accepted in 2014-08-19,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Pangilinan et al.; licensee BioMed Central Ltd.

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