Genotype-Tissue-Protein: proteomic variation and quantitative trait loci (pQTL)

描述（由申请人提供）：拟议研究的目标是系统地表征多种人体组织中的蛋白质组变异，并改进人类基因组的注释。利用微阵列或RNA-seq进行基因表达数量性状（eQTL）定位为人类生物学和解释全基因组关联研究（GWAS）的基因型-疾病关联结果提供了丰富的信息来源。相比之下，很少有工作研究蛋白质序列和丰度的变化，蛋白质组学变异的遗传基础仍然在很大程度上未被探索。这项研究的目的是量化蛋白质的丰度和编目蛋白质变体 在至少五个人体组织中使用先进的定量质谱分析平台。三个具体目标是（1）定量测量100个个体在五种组织中的蛋白质丰度，（2）表征变异并功能性注释组织特异性人类翻译组;（3）绘制影响蛋白质丰度的遗传变异（pQTL）。质谱数据将用于验证先前预测的编码蛋白质的基因间和内含子区域，并更好地注释人类基因组的翻译区。通过优先选择多组织供体，该项目最大限度地利用了GTEx资源，并提供了一个独特的机会，量化蛋白质的多样性和个体之间和跨组织的变化。蛋白质组变异代表RNA表达下游的分子表型，并可能提供RNA表达和表型之间的关键联系。我们期望pQTL定位分析可以捕获eQTL定位研究中未捕获的转录后调控机制。总之，这项研究中产生的新数据将对生物学和生物医学研究产生重要的积极影响，因为它们为解释通过全基因组关联研究确定的基因型-表型相关性提供了重要线索。他们还将验证人类转录组的注释，包括翻译起始位点的位置、剪接异构体多样性和异等位基因以及编辑表达。它们将为人类基因组界提供丰富的资源。最终，我们期望分子表型和注释的集合将提高我们预测个体疾病易感性的能力，并有助于设计个性化的预防和干预策略。

DESCRIPTION (provided by applicant): The goals of the proposed research are to systematically characterize proteomic variation in multiple human tissues and improve the annotation of the human genome. The mapping of gene expression quantitative traits (eQTL) using microarray or RNA-seq has provided a rich source of information for human biology and for interpreting genotype-disease association findings from genome-wide association studies (GWAS). In contrast, much less work has examined variation in protein sequence and abundance, and the genetic basis of proteomic variation remains largely unexplored. The objective of this research is to quantify the abundance of proteins and to catalog protein variants in at least five human tissues using an advanced quantitative mass-spectrometry-based platform. The three Specific Aims are to (1) Quantitatively measure protein abundance in 100 individuals across five tissues, (2) Characterize variation and functionally annotate the tissue-specific human translatome; and (3) Map genetic variation that influences protein abundance (pQTL). Mass spectrometry data will be used to verify previously predicted intergenic and intronic regions that encode protein, and to better annotate the translated region of the human genome. By preferentially selecting multi-tissue donors, this project maximizes the utilization of the GTEx resource and provides a unique opportunity for quantifying protein diversity and variation between individuals and across tissues. Proteomic variation represents a molecular phenotype downstream of RNA expression and may provide a critical link between RNA expression and phenotypes. We expect that the pQTL mapping analysis may capture post-transcriptional regulatory mechanisms that are not captured in eQTL mapping studies. Together, the new data generated in this research will have an important positive impact on biological and biomedical research, because they offer important clues for interpreting genotype-phenotype correlation identified through genome-wide association studies. They will also validate the annotation of the human transcriptome with regards to location of translation start sites, splice isoform diversity and heteroallele and editing expression. They will provide a rich resource for the human genome community. Ultimately, we expect the ensemble of molecular phenotypes and annotation will improve our ability for predicting an individual's disease susceptibility, as well as contribute to the design of individualized prevention and intervention strategies.