Evaluation of 64 candidate single nucleotide polymorphisms as risk factors for neural tube defects in a large Irish study population

Abstract

Individual studies of the genetics of neural tube defects (NTDs) contain results on a small number of genes in each report. To identify genetic risk factors for NTDs, we evaluated potentially functional single nucleotide polymorphisms (SNPs) that are biologically plausible risk factors for NTDs but that have never been investigated for an association with NTDs, examined SNPs that previously showed no association with NTDs in published studies, and tried to confirm previously reported associations in folate-related and non-folate-related genes. We investigated 64 SNPs in 34 genes for association with spina bifida in up to 558 case-families (520 cases, 507 mothers, 457 fathers) and 994 controls in Ireland. Case-control and mother-control comparisons of genotype frequencies, tests of transmission disequilibrium, and log-linear regression models were used to calculate effect estimates. Spina bifida was associated with over-transmission of the LEPR (leptin receptor) rs1805134 minor C allele (genotype relative risk (GRR): 1.5; 95% confidence interval (CI): 1.0, 2.1; P = 0.0264) and the COMT (catechol-O-methyltransferase) rs737865 major T allele (GRR: 1.4; 95% CI: 1.1, 2.0; P = 0.0206). After correcting for multiple comparisons, these individual test P-values exceeded 0.05. Consistent with previous reports, spina bifida was associated with MTHFR 677C>T, T (Brachyury) rs3127334, LEPR K109R, and PDGFRA promoter haplotype combinations. The associations between LEPR SNPs and spina bifida suggest a possible mechanism for the finding that obesity is a NTD risk factor. The association between a variant in COMT and spina bifida implicates methylation and epigenetics in NTDs.

Association between ALDH1L1 gene polymorphism and neural tube defects in the Chinese Han population

“…MTHFR plays an important role in the folate metabolism pathway and regulates the intracellular folate pool for synthesis and methylation of DNA folate metabolism [26]. It is investigated that the SNPs of MTHFR gene has a strong association with NTDs [27,28]. Spina bifida is a class of neural tube defects, it is reported that ALDH1L1 rs873696 and MTHFR rs1801133 are not risk factors of spina bifida [11].…”

Registries of cases with neural tube defects in Denizli, Turkey, 2004-2010

“…The geographical distribution of NTDs in Turkey indicates a relationship between the development of NTDs and socioeconomic and environmental factors. Although some polymorphisms leading to genetic effects have been demonstrated in studies worldwide (Botto and Yang, 2000;Pangilinan et al, 2010;Carter et al, 2011), the specific genes and genetic factors involved have yet to be determined. A 677C→T mutation in the methylenetetrahydrofolate reductase gene, which is thought to cause NTDs, is not a risk factor in the Turkish population (Boduroğlu et al, 1999).…”

“…Although Nanog3 upregulation is observed in 48%, Oct4 and Sox2 in 40% of the patients, the differences were not significant, only null mutation was significantly correlated with NTD (Saxena et al, 2013). The most common maternal risk factors associated with NTDs in infants include folic acid deficiency, overweight, diabetes, drugs, consanguinity, and single-nucleotide polymorphisms (Kondo et al, 2009;Herrmann and Obeid, 2011;Carter et al, 2011). The prevalence of NTDs at birth varies significantly by national geographical strata, ethnicity, and racial groups.…”

Exon sequencing of PAX3 and T (brachyury) in cases with spina bifida

“…Brachyury mutants) have defective mesoderm formation and abnormal axial development (Stott et al, 1993), and several studies have identified an association between a common variant in T (i.e. TIVS7-2, rs3127334) and the risk of neural tube defects in humans (Carter et al, 2011; Jensen et al, 2004; Morrison et al, 1996; Morrison et al, 1998; Shields et al, 2000). …”