Ritchie Marylyn D, Van Steen Kristel
Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
WELBIO, GIGA-R Medical Genomics Unit - BIO3, University of Liège, Liège, Belgium.
Ann Transl Med. 2018 Apr;6(8):157. doi: 10.21037/atm.2018.04.05.
One of the primary goals in this era of precision medicine is to understand the biology of human diseases and their treatment, such that each individual patient receives the best possible treatment for their disease based on their genetic and environmental exposures. One way to work towards achieving this goal is to identify the environmental exposures and genetic variants that are relevant to each disease in question, as well as the complex interplay between genes and environment. Genome-wide association studies (GWAS) have allowed for a greater understanding of the genetic component of many complex traits. However, these genetic effects are largely small and thus, our ability to use these GWAS finding for precision medicine is limited. As more and more GWAS have been performed, rather than focusing only on common single nucleotide polymorphisms (SNPs) and additive genetic models, many researchers have begun to explore alternative heritable components of complex traits including rare variants, structural variants, epigenetics, and genetic interactions. While genetic interactions are a plausible reality that could explain some of the heritabliy that has not yet been identified, especially when one considers the identification of genetic interactions in model organisms as well as our understanding of biological complexity, still there are significant challenges and considerations in identifying these genetic interactions. Broadly, these can be summarized in three categories: abundance of methods, practical considerations, and biological interpretation. In this review, we will discuss these important elements in the search for genetic interactions along with some potential solutions. While genetic interactions are theoretically understood to be important for complex human disease, the body of evidence is still building to support this component of the underlying genetic architecture of complex human traits. Our hope is that more sophisticated modeling approaches and more robust computational techniques will enable the community to identify these important genetic interactions and improve our ability to implement precision medicine in the future.
精准医学时代的主要目标之一是了解人类疾病的生物学特性及其治疗方法，以便每个患者都能根据其遗传和环境暴露情况获得针对其疾病的最佳治疗。朝着实现这一目标努力的一种方法是确定与每种相关疾病相关的环境暴露和基因变异，以及基因与环境之间的复杂相互作用。全基因组关联研究（GWAS）使人们对许多复杂性状的遗传成分有了更深入的了解。然而，这些遗传效应大多较小，因此我们将这些GWAS发现用于精准医学的能力有限。随着越来越多的GWAS研究开展，许多研究人员开始探索复杂性状的替代遗传成分，而不仅仅关注常见的单核苷酸多态性（SNP）和加性遗传模型，这些替代成分包括罕见变异、结构变异、表观遗传学和基因相互作用。虽然基因相互作用是一个合理的现实，能够解释一些尚未被识别的遗传力，特别是当考虑到在模式生物中基因相互作用的识别以及我们对生物复杂性的理解时，但识别这些基因相互作用仍存在重大挑战和需要考虑的因素。大致来说，这些可以归纳为三类：方法的丰富性、实际考虑因素和生物学解释。在这篇综述中，我们将讨论在寻找基因相互作用过程中的这些重要因素以及一些潜在的解决方案。虽然从理论上理解基因相互作用对复杂人类疾病很重要，但支持复杂人类性状潜在遗传结构这一组成部分的证据仍在不断积累。我们希望更复杂的建模方法和更强大的计算技术将使科学界能够识别这些重要的基因相互作用，并提高我们未来实施精准医学的能力。
