PheWAS of Loss-of-Function Variants

 描述(由申请人提供)：通过全基因组关联研究(GWAS)致力于复杂疾病的研究。然而，由于几个限制，GWAS提供的医学上可操作的结果很少。当大多数被检测的SNP没有已知的功能和/或被认为是未分型或未表征的功能变体的标签时，GWAS方法的一个局限性是难以识别功能变体。第二个限制是缺乏遗传性或缺乏对环境因素对正在研究的疾病的影响。有必要采用替代的和补充的方法来替代全球气候变化分析技术。一种解决这些局限性的新策略包括使用电子医疗记录(EMR)来进行表型全组关联研究(Phewas)，当确定了合理的遗传目标时。而Gwas问的是“哪些基因变异与一种疾病有关？”Phewas问道：“哪些疾病与基因变异有关？”该项目正在测试的假设是，功能丧失变异--临床相关概率最高的O类变异--可能会导致EMR中描述的疾病表型。为了验证这一假设，我们提出了以下具体目标：(1)测量10,000名Marshfield Clinic患者EMR中编码的数千种疾病表型与功能丧失SNPs之间的关联；(2)在独立队列中重复发现；以及(3)通过使用患者生物标本、细胞系和动物模型系统的功能基因组实验，调查这些关联的生物学相关性。这项研究的结果将把基于联想的测试与生物实验结合起来。因此，这项研究不仅在方法上是创新的，而且在同时评估许多疾病的遗传成分方面也是创新的，包括研究不足的疾病。此外，Phewas方法有能力表征具有共同遗传病因的多种疾病。这对于“药物再利用”可能很重要，因为用于治疗一种疾病的药物也可能对另一种疾病具有治疗作用，如果两者都有共同的基因联系的话。

 DESCRIPTION (provided by applicant): Significant effort has been dedicated to the study of complex diseases through genome-wide association studies (GWASs). However, GWASs have provided few medically actionable results due to several limitations. One limitation of the GWAS approach is the difficulty in identifying functional variants when most assayed SNPs have no known function and/or are considered tags for an ungenotyped or uncharacterized functional variant. A second limitation is the lack of heritability or appreciation for the environmental contribution to the disease under study. Alternative and complementary approaches to the GWAS technique are necessary. A novel strategy to address these limitations includes the use of electronic medical records (EMRs) to conduct a phenome-wide association study (PheWAS) when plausible genetic targets are identified. Whereas GWAS asks "What genetic variants are associated with a disease?" PheWAS asks "What diseases are associated with a genetic variant?" The hypothesis being tested in this project is that loss-of-function variants - a class o variation with the highest probability of being clinically relevant - may cause disease phenotypes described in EMRs. To test this hypothesis, we propose the following specific aims: (1) measure associations between thousands of disease phenotypes coded in the EMR for 10,000 Marshfield Clinic patients and loss-of-function SNPs, (2) replicate findings in an independent cohort, and (3) investigate the biological relevance of these associations through functional genomic experiments using patient biospecimens, cell lines, and animal model systems. The results from this study will combine association-based testing with biological experimentation. Therefore, this study is not only innovative in its approach, but also in its capacity to assess the genetic component of many diseases simultaneously, including understudied diseases. In addition, the PheWAS approach has the capacity to characterize multiple diseases that share a common genetic etiology. This may be important for "drug repurposing," in that drugs used to treat one disease may also be therapeutic for a different disease, if both share a common genetic link.