Investigation of potential gene-gene interactions between APOE and RELN contributing to autism risk
Investigation of potential gene-gene interactions between APOE and RELN contributing to autism risk
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DOI：
10.1097/ypg.0b013e32809c2f75
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发表时间：
2007-08-01
影响因子：
0.9
通讯作者：
Pericak-Vance, Margaret A.
中科院分区：
文献类型：
--
作者：
Ashley-Koch, Allison E.;Jaworski, James;Pericak-Vance, Margaret A.
背景一些候选基因的研究结果支持BLON是孤独症的易感基因。鉴于自闭症复杂的遗传模式，预计基因间的相互作用将存在。研究潜在的基因-基因相互作用的一个逻辑起点是评估共同生物学途径中涉及的基因的联合效应。目的探讨APOE-2等位基因在孤独症易感性中的联合作用。方法对470个白种人孤独症家系（265个多重家系，168个无家族史的三重家系，37个有家族史但仅有1个样本受累的家系）进行分析。对这些家族进行了11个APOE多态性的基因分型，包括先前与自闭症相关的5'非翻译区重复序列，以及APOE功能等位基因。我们分别用家系不平衡检验和基因PDT评估了单位点等位基因和基因型的关联。多位点的影响进行了评估，使用扩展版本的多因子降维方法。结果对于单位点分析，没有证据表明在我们的数据集的APOE的效果。然而，有证据表明，APOE基因型与APOE N rs 2073559相关（rs 2073559;三个亚组P = 0.07 PDT; P = 0.001基因PDT;总体基因PDT P = 0.05），对于多位点基因PDT分析，APOE和APOE N rs 2073559的联合基因型非常显著（三个亚组总体P = 0.0001），可能是由APOE N单位点效应驱动的。使用扩展版本的多因子降维方法检测多位点效应，在总体或多重亚组中，涉及APOE或APON的任何n位点组合均无统计学显著相关性。在三个亚组中，1-位点和2-位点模型仅选择了CRISON中的标记作为预测自闭症病例的最佳模型。结论因此，我们得出结论，在我们的自闭症数据集中没有APOE的主要作用，也没有任何证据表明APOE与CRISON的联合作用。然而，CANN仍然是自闭症易感性的一个很好的候选者。
Background Several candidate gene studies support RELN as susceptibility gene for autism. Given the complex inheritance pattern of autism, it is expected that gene-gene interactions will exist. A logical starting point for examining potential gene-gene interactions is to evaluate the joint effects of genes involved in a common biological pathway. RELN shares a common biological pathway with APOE, and Persico et al have observed transmission distortion of the APOE-2 allele in autism families.Objective We evaluated RELN and APOE for joint effects in autism susceptibility.Methods A total of 470 Caucasian autism families were analyzed (265 multiplex; 168 trios with no family history; 37 positive family history but only one sampled affected). These families were genotyped for 11 RELN polymorphisms, including the 5' untranslated region repeat previously associated with autism, as well as for the APOE functional allele. We evaluated single locus allelic and genotypic association with the pedigree disequilibrium test and geno-PDT, respectively. Multilocus effects were evaluated using the extended version of the multifactorial dimensionality reduction method.Results For the single locus analyses, there was no evidence for an effect of APOE in our data set. Evidence for association with RELN (rs2073559; trio subset P = 0.07 PDT; P = 0.001 geno-PDT; overall geno-PDT P = 0.05), however, was found. For multilocus geno-PDT analysis, the joint genotype of APOE and RELN rs2073559 was highly significant (trio subset global P = 0.0001), probably driven by the RELN single locus effect. Using the extended version of the multifactorial dimensionality reduction method to detect multilocus effects, there were no statistically significant associations for any of the n-locus combinations involving RELN or APOE in the overall or multiplex subset. In the trio subset 1-locus and 2-locus models selected only markers in RELN as best models for predicting autism caseConclusion Thus, we conclude that there is no main effect of APOE in our autism data set, nor is there any evidence for a joint effect of APOE with RELN. RELN, however, remains a good candidate for autism susceptibility.