Abstract：
Recent studies have highlighted the essential role of RNA splicing, a key mechanism of alternative RNA processing, in establishing connections between genetic variations and disease. Genetic loci influencing RNA splicing variations show considerable influence on complex traits, possibly surpassing those affecting total gene expression. Dysregulated RNA splicing has emerged as a major potential contributor to neurological and psychiatric disorders, likely due to the exceptionally high prevalence of alternatively spliced genes in the human brain. Nevertheless, establishing direct associations between genetically altered splicing and complex traits has remained an enduring challenge. We introduce Spliced-Transcriptome-Wide Associations (SpliTWAS) to integrate alternative splicing information with genome-wide association studies to pinpoint genes linked to traits through exon splicing events. We applied SpliTWAS to two schizophrenia (SCZ) RNA-sequencing datasets, BrainGVEX and CommonMind, revealing 137 and 88 trait-associated exons (in 84 and 67 genes), respectively. Enriched biological functions in the associated gene sets converged on neuronal function and development, immune cell activation, and cellular transport, which are highly relevant to SCZ. SpliTWAS variants impacted RNA-binding protein binding sites, revealing potential disruption of RNA-protein interactions affecting splicing. We extended the probabilistic fine-mapping method FOCUS to the exon level, identifying 36 genes and 48 exons as putatively causal for SCZ. We highlight VPS45 and APOPT1, where splicing of specific exons was associated with disease risk, eluding detection by conventional gene expression analysis. Collectively, this study supports the substantial role of alternative splicing in shaping the genetic basis of SCZ, providing a valuable approach for future investigations in this area.
摘要：
最近的研究强调了RNA剪接的重要作用，替代RNA加工的关键机制，在遗传变异和疾病之间建立联系。影响RNA剪接变异的遗传基因座对复杂性状显示出相当大的影响，可能超过影响总基因表达的那些。RNA剪接失调已经成为神经和精神疾病的主要潜在因素。可能是由于人类大脑中选择性剪接基因的患病率异常高。然而，在遗传改变的剪接和复杂性状之间建立直接关联仍然是一个持久的挑战。我们引入了剪接转录组广泛关联（SpliTWAS），以将可变剪接信息与全基因组关联研究整合，以通过外显子剪接事件确定与性状相关的基因。我们将SpliTWAS应用于两个精神分裂症（SCZ）RNA测序数据集，BrainGVEX和CommonMind,揭示137和88个性状相关外显子（在84和67个基因中），分别。丰富的生物学功能在相关的基因集中集中在神经元的功能和发育，免疫细胞激活，和细胞运输，与SCZ高度相关。SpliTWAS变体影响RNA结合蛋白结合位点，揭示影响剪接的RNA-蛋白质相互作用的潜在破坏。我们将概率精细映射方法FOCUS扩展到外显子水平，鉴定36个基因和48个外显子作为SCZ的推定因果关系。我们重点介绍了VPS45和APOPT1，其中特定外显子的剪接与疾病风险有关，通过常规基因表达分析进行逃避检测。总的来说，这项研究支持选择性剪接在塑造SCZ遗传基础中的重要作用，为该领域的未来调查提供了宝贵的方法。
