Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants.
Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants.
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DOI：
10.1186/s13229-015-0034-z
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发表时间：
2015
期刊：
影响因子：
6.2
通讯作者：
Pericak-Vance MA
中科院分区：
文献类型：
--
作者：
Griswold AJ;Dueker ND;Van Booven D;Rantus JA;Jaworski JM;Slifer SH;Schmidt MA;Hulme W;Konidari I;Whitehead PL;Cuccaro ML;Martin ER;Haines JL;Gilbert JR;Hussman JP;Pericak-Vance MA
自闭症谱系障碍（ASD）具有高度遗传性，但全基因组关联研究（GWAS），拷贝数变异筛选和候选基因关联研究发现，没有单一因素占遗传风险的很大比例。ASD三外显子组测序研究揭示了具有复发性从头功能丧失变体的基因是强风险因素，但复发性受影响的基因相对较少，而预计多达1000个基因起作用。因此，识别导致ASD的其余罕见和低频变体至关重要。我们采用了GWAS基因优先排序的方法，并在病例对照队列中进行大规模平行测序。使用先前报道的ASD降噪GWAS分析，我们优先考虑837个RefSeq基因用于定制靶向和测序。我们对2071例ASD病例和904例欧洲白色血统对照者的这些基因的编码区进行了测序。我们应用全面的注释来识别可能赋予ASD风险的单个变异，并应用基于基因的关联分析来识别与ASD相关的罕见变异集。我们在先前与ASD相关的基因中发现了罕见的功能丧失变体的显著过度表达，包括在已确立的ASD候选基因RBFOX 1中的从头过早终止变体。此外，ASD病例比对照组更可能在候选基因中具有两个破坏性错义变体。最后，基于基因的罕见变异关联涉及在兴奋性神经传递和神经突生长和指导途径中起作用的基因，包括CACNAD 2，KCNH 7和NRXN 1。我们发现提示性证据表明，突触基因的罕见变异与ASD相关，ASD候选基因的功能丧失突变是一个主要的风险因素，我们暗示谷氨酸信号受体和神经元粘附和引导分子的破坏性突变。此外，新生突变在ASD中的作用仍有待充分研究，因为我们在ASD中首次发现了RBFOX 1中的蛋白质截短变体。总的来说，这项工作，结合其他人在该领域，提出了一个融合的基因和分子途径的ASD病因。本文的在线版本（doi：10.1186/s13229-015-0034-z）包含补充材料，可供授权用户使用。
Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. We have utilized an approach of prioritization of genes by GWAS and follow-up with massively parallel sequencing in a case-control cohort. Using a previously reported ASD noise reduction GWAS analyses, we prioritized 837 RefSeq genes for custom targeting and sequencing. We sequenced the coding regions of those genes in 2071 ASD cases and 904 controls of European white ancestry. We applied comprehensive annotation to identify single variants which could confer ASD risk and also gene-based association analysis to identify sets of rare variants associated with ASD. We identified a significant over-representation of rare loss-of-function variants in genes previously associated with ASD, including a de novo premature stop variant in the well-established ASD candidate gene RBFOX1. Furthermore, ASD cases were more likely to have two damaging missense variants in candidate genes than controls. Finally, gene-based rare variant association implicates genes functioning in excitatory neurotransmission and neurite outgrowth and guidance pathways including CACNAD2, KCNH7, and NRXN1. We find suggestive evidence that rare variants in synaptic genes are associated with ASD and that loss-of-function mutations in ASD candidate genes are a major risk factor, and we implicate damaging mutations in glutamate signaling receptors and neuronal adhesion and guidance molecules. Furthermore, the role of de novo mutations in ASD remains to be fully investigated as we identified the first reported protein-truncating variant in RBFOX1 in ASD. Overall, this work, combined with others in the field, suggests a convergence of genes and molecular pathways underlying ASD etiology. The online version of this article (doi:10.1186/s13229-015-0034-z) contains supplementary material, which is available to authorized users.