Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
BMC Med Genet. 2012 Aug 2;13:62. doi: 10.1186/1471-2350-13-62.
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.
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.
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.
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.
神经管缺陷（NTDs）是一种常见的出生缺陷（在美国和欧洲，约每 1000 例妊娠中就有 1 例），其发病机制复杂，涉及环境和遗传因素。母体叶酸水平低是一个公认的危险因素，母体围孕期补充叶酸可使 NTD 妊娠的发生率降低 50-70%。叶酸代谢途径中的基因变异（例如 MTHFR rs1801133（677 C > T）和 MTHFD1 rs2236225（R653Q））已被发现增加了 NTD 的风险。我们假设，叶酸/B12 途径中其他基因的变异也与 NTD 风险有关。
采用标签 SNP 方法筛选了叶酸/B12 途径和 NTD 小鼠模型中 82 个候选基因中的常见变异。我们首先对 320 个爱尔兰三核苷酸（NTD 病例及其父母）进行了多态性分析，其中包括 301 例病例和 341 例爱尔兰对照，以进行病例对照和基于家庭的关联检验。在包括 229 例病例和 658 例对照的 250 个二级家系中对显著相关的多态性进行了基因分型。对 1441 个 SNP 的联合结果进行了联合分析，以检验病例和母体效应。
在 p < 0.01 的水平上，有近 70 个 SNP 在 30 个基因中与 NTD 相关。在九个基因（MFTC、CDKN2A、ADA、PEMT、CUBN、GART、DNMT3A、MTHFD1 和 T（Brachyury））中发现了十个最强的关联信号（p 值范围：0.0003-0.0023），其中包括已知的 NTD 风险因素 MTHFD1 R653Q（rs2236225）。在一个新的候选基因 MFTC rs17803441 中观察到最强的信号（OR = 1.61 [1.23-2.08]，p = 0.0003 为次要等位基因）。尽管这些关联具有统计学意义，但在进行多次假设检验校正后，这些关联不再显著。
据我们所知，就样本量和候选多态性评估范围而言，这是迄今为止报道的最大的 NTD 遗传关联研究。研究的规模和校正的严格性可能导致真正的关联无法通过校正而幸存下来。我们已经生成了一个具有最强关联信号的变异体的排序列表。具有最高关联等级的变体可能包含真实的关联，应成为进一步研究 NTD 风险的高优先级候选者。
