An Integrated Meta-Analysis of Two Variants in HOXA1/HOXB1 and Their Effect on the Risk of Autism Spectrum Disorders

BackgroundHOXA1 and HOXB1 have been strongly posed as candidate genes for autism spectrum disorders (ASD) given their important role in the development of hindbrain. The A218G (rs10951154) in HOXA1 and the insertion variant in HOXB1 (nINS/INS, rs72338773) were of special interest for ASD but with inconclusive results. Thus, we conducted a meta-analysis integrating case-control and transmission/disequilibrium test (TDT) studies to clearly discern the effect of these two variants in ASD. Methods and FindingsMultiple electronic databases were searched to identify studies assessing the A218G and/or nINS/INS variant in ASD. Data from case-control and TDT studies were analyzed in an allelic model using the Catmap software. A total of 10 and 7 reports were found to be eligible for meta-analyses of A218G and nINS/INS variant, respectively. In overall meta-analysis, the pooled OR for the 218G allele and the INS allele was 0.97 (95% CI = 0.76-1.25, Pheterogeneity = 0.029) and 1.14 (95% CI = 0.97-1.33, Pheterogeneity = 0.269), respectively. No significant association was also identified between these two variants and ASD risk in stratified analysis. Further, cumulative meta-analysis in chronologic order showed the inclination toward null-significant association for both variants with continual adding studies. Additionally, although the between-study heterogeneity regarding the A218G is not explained by study design, ethnicity, and sample size, the sensitive analysis indicated the stability of the result. ConclusionsThis meta-analysis suggests the HOXA1 A218G and HOXB1 nINS/INS variants may not contribute significantly to ASD risk.

研究背景 鉴于同源框A1（HOXA1）与同源框B1（HOXB1）在后脑发育中发挥关键作用，二者被强烈推荐为自闭症谱系障碍（ASD）的候选基因。针对HOXA1的A218G位点（rs10951154）与HOXB1的插入变异（nINS/INS，rs72338773），既往相关ASD研究结果均未得出明确结论。为此，本研究开展荟萃分析，整合病例对照研究与传递不平衡检验（TDT），以明确上述两种变异在ASD发病中的作用。研究方法与结果 检索多个电子数据库，筛选评估HOXA1 A218G和/或HOXB1 nINS/INS变异与ASD关联的相关研究。采用Catmap软件，以等位基因模型对病例对照及TDT研究的数据进行分析。最终分别纳入10篇与7篇符合荟萃分析标准的A218G、nINS/INS变异相关研究。整体荟萃分析结果显示，218G等位基因与INS等位基因的合并比值比（OR）分别为0.97（95%置信区间[CI]：0.76~1.25，异质性P值=0.029）与1.14（95%CI：0.97~1.33，异质性P值=0.269）。分层分析中，未发现这两种变异与ASD患病风险存在显著关联。进一步按时间顺序开展的累积荟萃分析显示，随着研究不断纳入，两种变异与ASD的关联均倾向于无统计学意义。此外，尽管A218G位点的研究间异质性无法通过研究设计、种族与样本量进行解释，但敏感性分析结果表明本研究结论具有稳定性。研究结论 本项荟萃分析提示，HOXA1 A218G与HOXB1 nINS/INS变异可能并未对ASD患病风险产生显著影响。