Association and gene-gene interaction of SLC6A4 and ITGB3 in autism.
Association and gene-gene interaction of SLC6A4 and ITGB3 in autism.
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DOI：
10.1002/ajmg.b.31003
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发表时间：
2010-03-05
影响因子：
2.8
通讯作者：
Martin, E. R.
中科院分区：
文献类型：
--
作者：
Ma, D. Q.;Rabionet, R.;Konidari, I.;Jaworski, J.;Cukier, H. N.;Wright, H. H.;Abramson, R. K.;Gilbert, J. R.;Cuccaro, M. L.;Pericak-Vance, M. A.;Martin, E. R.
自闭症是一种具有遗传异质性的遗传性神经发育障碍。研究指出自闭症与两种血清素相关基因SLC6A4和ITGB3之间可能存在联系，这两种基因具有性别特异性的遗传效应和基因之间的相互作用。尽管有积极的发现，但不一致的结果使解释变得复杂。本研究旨在验证和澄清先前在考虑性别、家族史（FH）和基因效应的独立数据集中的发现。对每个基因进行基于家族的关联分析。使用扩展多因素降维（EMDR）和耐多药表型组学，以受影响性别和FH为协变量，测试基因-基因相互作用。在按性别分层的数据集中，没有发现与个体snp的显著关联，但当我们按家族史分层时，确实出现了关联。虽然在整个数据集中不显著，但在FH -（家族史阴性）家族中，SLC6A4的RS2066713位点（p=0.006）与FH -（家族史阳性）家族中的RS2066713位点（p=0.038）存在名义上显著的关联，但与FH -家族中相反的风险等位基因。对于ITGB3，总体上在RS3809865位点（p= 0.040）和FH+家族内（p=0.031）发现了名义上显著的关联。然而，没有一个关联在多次测试修正中幸存下来。耐多药表型组学以受影响性别（p=0.023）和家族史（p=0.014，经多次检验校正后存活）作为协变量证实了基因-基因效应。我们的研究结果表明，这两个基因在不同的家族中存在广泛的异质性。SLC6A4和ITGB3之间潜在的相互作用，特别是家族史作为一种有希望的遗传结构指标，进一步说明了协变量作为遗传分析异质性标记的重要性。
Autism is a heritable neurodevelopmental disorder with substantial genetic heterogeneity. Studies point to possible links between autism and two serotonin related genes: SLC6A4 and ITGB3 with a sex-specific genetic effect and interaction between the genes. Despite positive findings, inconsistent results have complicated interpretation. This study seeks to validate and clarify previous findings in an independent dataset taking into account sex, family-history (FH) and gene-gene effects. Family-based association analysis was performed within each gene. Gene-gene interactions were tested using extended multifactor dimensionality reduction (EMDR) and MDR-phenomics using sex of affecteds and FH as covariates. No significant associations with individual SNPs were found in the datasets stratified by sex, but associations did emerge when we stratified by family history. While not significant in the overall dataset, nominally significant association was identified at RS2066713 (p=0.006) within SLC6A4 in FH− (family-history negative) families, at RS2066713 (p=0.038) in FH+ (family-history positive) families but with the opposite risk allele as in the FH− families. For ITGB3, nominally significant association was identified at RS3809865 overall (p= 0.040) and within FH+ families (p=0.031). However, none of the association survived the multiple testing corrections. MDR-phenomics confirmed gene-gene effects using sex of affecteds (p=0.023) and family history (p=0.014, survived the multiple testing corrections) as covariates. Our results indicate the extensive heterogeneity within these two genes among families. The potential interaction between SLC6A4 and ITGB3, particularly family history as a promising indicator of genetic architecture further illustrates the importance of covariates as markers of heterogeneity into genetic analyses.
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