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），已致力于复杂疾病的研究。然而，由于一些限制，GWAS提供了很少的医学可操作的结果。GWAS方法的一个限制是当大多数测定的SNP不具有已知功能和/或被认为是未基因分型或未表征的功能变体的标签时，难以鉴定功能变体。第二个限制是缺乏遗传性或对所研究疾病的环境贡献的认识。GWAS技术的替代和补充方法是必要的。解决这些局限性的新策略包括使用电子病历（EMR）进行全表型关联研究（PheWAS），当确定了合理的遗传靶点时。而GWAS问的是“什么样的遗传变异与疾病有关？PheWAS问道：“哪些疾病与遗传变异有关？”“在这个项目中正在测试的假设是，功能丧失变异-一种具有最高临床相关概率的o类变异-可能导致EMR中描述的疾病表型。为了检验这一假设，我们提出了以下具体目标：（1）测量10，000名Marshfield诊所患者的EMR中编码的数千种疾病表型与功能丧失SNP之间的关联，（2）在独立队列中重复发现，以及（3）通过使用患者生物样本、细胞系、和动物模型系统。本研究的结果将结合联合收割机相关性测试和生物学实验。因此，这项研究不仅在方法上具有创新性，而且能够同时评估许多疾病的遗传成分，包括研究不足的疾病。此外，PheWAS方法能够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，因为如果两种药物都有共同的遗传联系，那么用于治疗一种疾病的药物也可能用于治疗另一种疾病。

 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.