Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders.
Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders.
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DOI：
10.1371/journal.pgen.1006516
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发表时间：
2017-01
期刊：
影响因子：
4.5
通讯作者：
Weiss LA
中科院分区：
文献类型：
--
作者：
Mitra I;Lavillaureix A;Yeh E;Traglia M;Tsang K;Bearden CE;Rauen KA;Weiss LA
尽管基因-基因相互作用或上位性在模式生物的复杂性状中起着重要作用，但全基因组范围内的双向相互作用搜索在人类研究中的作用有限。因此，我们使用生物学途径的知识，以确定上位性对人类自闭症谱系障碍（ASD）的贡献，这是一种反向途径遗传学方法。基于先前对Ras/MAPK通路的孟德尔疾病（RASopathies）中ASD症状增加的观察，我们发现RASopathy基因中的常见SNP显示GWAS中关联信号的富集（P = 0.02）。然后，我们在全基因组范围内筛选了具有RASopathy基因SNP的相互作用者，并在ASD受影响的个体中显示出强烈的富集（P < 2.2 x 10−16），许多成对相互作用符合全基因组的显著性标准。最后，我们利用RASopathy影响的个人ASD症状的定量措施，通过GWAS进行修饰符映射。一个顶部区域在这些独立的方法之间重叠，我们在RASopathy神经细胞系中显示了该区域的基因GPR 141的失调。因此，我们使用正交的方法来提供强有力的证据，上位性ASD的贡献，确认Ras/MAPK通路在特发性ASD的作用，并确定一个收敛的候选基因，可能与Ras/MAPK通路相互作用。上位性对人类生物学和复杂性状结构的贡献一直受到激烈的争论。尽管有统计学方法来检测相互作用，等位基因频率和研究设计限制了我们解决这个问题的能力。我们开发了一种反向途径遗传学方法来检测自闭症谱系障碍（ASD）中的上位性，而不是一种基于遗传学动机的方法。而不是传统的途径分析，利用公正的遗传结果，以确定重要的病理生理学的生物途径，我们假设，利用一个特定的生物途径，发现新的方面的遗传结构的反向方法可能是富有成效的。我们从与ASD相关的Ras/MAPK通路的孟德尔疾病（RASopathies）中汲取知识，为我们的分析提供信息。首先，我们在特发性ASD中实施了与Ras/MAPK通路相互作用的SNP的上位性筛选，使我们能够检测上位性信号以及特定相互作用位点的全基因组富集。其次，我们在RASopathies中进行了修饰符映射，并使用我们的第一种方法识别了重叠信号。最后，我们采用顶部重叠区域，并通过实验证明来自RAS病受试者的iPSC衍生的神经细胞中的表达失调。总之，我们的研究结果建立了一个人类遗传学驱动的反向途径策略，可以广泛应用于上位性研究。
Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway. The contribution of epistasis to human biology and complex trait architecture has been subject to intense debate. Despite statistical methods to detect interaction, allele frequencies and study designs have limited our power to address this question. Rather than a statistically-motivated approach, we developed a reverse pathway genetic approach to detect epistasis in in autism spectrum disorders (ASDs). Instead of traditional pathway analysis—exploiting unbiased genetic results to identify biological pathways important for pathophysiology—we hypothesized that the reverse approach of leveraging a specific biological pathway to uncover novel aspects of genetic architecture could be fruitful. We drew on knowledge from Mendelian disorders of the Ras/MAPK pathway (RASopathies) associated with ASD to inform our analyses. First, we implemented an epistasis screen in idiopathic ASD for SNPs that interact with the Ras/MAPK pathway, allowing us to detect genome-wide enrichment in epistasis signal as well as specific interacting loci. Second, we performed modifier mapping within RASopathies and identified overlapping signals with our first approach. Finally, we took the top overlapping region and experimentally demonstrated dysregulated expression in iPSC-derived neural cells from RASopathy subjects. Together, our results establish a human genetics motivated reverse-pathway strategy, which can be applied broadly to study epistasis.