Methods for linking GWAS peaks to function in psychiatric disease

 描述(申请人提供)：全基因组关联研究在识别与精神分裂症和其他精神疾病相关的变异方面非常成功，但这些变异的分子影响在很大程度上仍不清楚。与此同时，ENCODE、路线图表观基因组学和其他项目产生了功能数据的爆炸性增长，使开发新的统计方法将遗传数据中的关联与来自功能数据的生物学解释联系起来成为当务之急。我们的具体目标是：1)按功能类别划分精神疾病的遗传性。我们建议在全球水平上理解解释精神疾病遗传性的不同类别变异的相对重要性。2)最大限度地利用脑组织中的表达数据进行生物学推断。我们建议扩展现有的处理和分析RNA测序数据的方法，以改进影响表达水平和剪接多样性的数量性状基因座的识别。3)使用优先功能类别和QTL精细定位全基因组显著基因座。我们将整合AIMS 1和AIMS 2的结果，以更彻底地了解哪些基因变异导致全基因组范围内与精神疾病的显著关联。我们将使用来自全基因组相关精神疾病研究的20万个样本来指导我们的研究。我们建议开发的方法将在软件包中实现，我们将向社会广泛提供这些软件包。

 DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have been extremely successful in identifying variants associated to schizophrenia and other psychiatric disorders, but the molecular impact of these variants remains largely unknown. Meanwhile, an explosion of functional data has been generated by ENCODE, ROADMAP Epigenomics and other projects, making the development of new statistical methods to link associations in genetic data to biological interpretations from functional data a pressing priority Our specific aims are 1) To partition psychiatric disease heritability by functional category. We propose to understand at a global level the relative importance of different classes of variation i explaining heritability of mental illness. 2) To maximize biological inferences from expression data in brain tissues. We propose to extend current methods for the processing and analysis of RNA-sequencing data to improve identification of quantitative trait loci that influence expression levels and splicing diversity. 3) To use prioritized functional categories and QTLs to fine-map genome-wide significant loci. We will integrate the results of aims 1 and 2 to more thoroughly understand which genetic variants drive genome-wide significant associations to mental illness. We will guide our research using >200,000 samples from genome-wide associations studies of psychiatric disease. The methods we propose to develop will be implemented in software packages that we will make widely available to the community.