Context matters: Network modeling of COPD regulatory variants across tissues and exposures

项目摘要/摘要 在过去的十年里，在识别具有疾病风险的基因变异方面取得了快速进展。然而， 这些变异体发挥影响的生物学背景还没有完全被理解。例如，香烟 吸烟是慢性阻塞性肺疾病(COPD)的主要危险因素；然而，只有 吸烟者会患上COPD，这表明基因可能在COPD的发病机制中起作用。基因组- 广泛的关联研究已经确定了20多个与COPD状态相关的遗传位点。然而， 这些单核苷酸多态(SNPs)只能解释一小部分的表型变异 慢性阻塞性肺疾病（慢阻肺）。这表明许多弱表型效应的变种共同作用影响COPD 病理生物学。 肺遗传学家现在面临的挑战之一是了解这许多SNP是如何共同作用的 影响生物功能，并确定这些功能在哪些情况下是重要的。考虑到 与疾病相关的SNP通常不会改变蛋白质编码，这些SNP可能会影响细胞的表型 通过对基因表达的调控。 我们建议开发新的监管网络模型来模拟疾病的集体效应- 与组织和暴露相关的SNP，如香烟烟雾。然后我们将应用这些方法 为了更好地了解与COPD相关的变异体的上下文特定调控功能。 普拉蒂格博士在物理学、复杂系统和基因组学方面的培训为他完成这项工作做好了充分的准备 研究。然而，在统计遗传学、功能基因组学、网络理论和 肺部生物学将有助于他的科学和专业发展，因为他开始在 2018年夏天网络医学(CDNM)昌宁分部。结合正式的课程作业， 通过密集的研讨会和跨学科的指导，普拉蒂格博士将获得必要的技能，以实现他的 目标。 CDNM和哈佛医学院为研究和培训提供了绝佳的机会 肺部疾病的系统遗传学，五年内有四所教学医院和两所哈佛大学 街区半径。Platig博士将通过他的主要导师Dr。 西尔弗曼和他的合作导师夸肯布什博士。此外，普拉蒂格博士还将出席与 肺病学家、统计遗传学家和内科医生定期获得关于他的研究和培训的反馈。这 研究和培训的结合将使Platig博士为发现和应对 肺部疾病的系统遗传学。

Project Abstract/Summary The last decade has seen rapid progress in identifying genetic variants that confer disease risk. However, the biological context in which these variants exert their influence is not fully understood. For example, cigarette smoke is a major risk factor for chronic obstructive pulmonary disease (COPD); however, only a subset of smokers develop COPD, suggesting that genetics may play a role in the pathogenesis of COPD. Genome- wide association studies have identified more than twenty genetic loci associated with COPD status. However, these single nucleotide polymorphisms (SNPs) only explain a small amount of the phenotypic variance of COPD. This suggests that many variants of weak phenotypic effect work together to influence COPD pathobiology. One of the challenges now for pulmonary geneticists is to understand how these many SNPs work together to influence biological function, and to identify the contexts in which those functions are important. Given that disease-associated SNPs often do not alter protein coding, these SNPs likely influence cellular phenotypes through regulatory control of gene expression. We propose to develop new regulatory network models for modeling the collective effect of disease- associated SNPs across tissues and on exposures such as cigarette smoke. We will then apply these methods to better understand the context-specific regulatory function of variants associated with COPD. Dr. Platig’s training in physics, complex systems, and genomics has well prepared him to carry out this research. However, additional training in statistical genetics, functional genomics, network theory, and pulmonary biology will aid in his scientific and professional development as he starts his faculty position at the Channing Division of Network Medicine (CDNM) in the summer of 2018. With a blend of formal coursework, intensive workshops, and interdisciplinary mentoring, Dr. Platig will obtain the necessary skills to achieve his goals. The CDNM and Harvard Medical School provide outstanding opportunities for research and training in the systems genetics of pulmonary disease, with four teaching hospitals and two Harvard schools within a five block radius. Dr. Platig will have access to extensive computing resources through his primary mentor, Dr. Silverman, and through his co-mentor Dr. Quackenbush. In addition, Dr. Platig will attend regular meetings with pulmonologists, statistical geneticists, and physicians to get regular feedback on his research and training. This combination of research and training will prepare Dr. Platig for identifying and tackling the open challenges in the systems genetics of pulmonary disease.