Wellcome Sanger Institute, Cambridge CB10 1HH, United Kingdom; email:
Annu Rev Genomics Hum Genet. 2018 Aug 31;19:97-112. doi: 10.1146/annurev-genom-083117-021641. Epub 2018 May 25.
Genome-wide association studies (GWASs) have revolutionized human disease genetics by discovering tens of thousands of associations between common variants and complex diseases. In parallel, huge technological advances in DNA sequencing have made it possible to measure and analyze rare variation in populations. This review considers these two stories and how they have come together. We first review the history of GWASs and sequencing. We then consider how to understand the biological mechanisms that drive signals of strong association in the absence of rare-variant studies. We describe how rare-variant studies complement these approaches and highlight both data generation and statistical challenges in their interpretation. Finally, we consider how certain special study designs, such as those for families and isolated populations, fit in this paradigm.
全基因组关联研究 (GWAS) 通过发现成千上万种常见变异与复杂疾病之间的关联，彻底改变了人类疾病遗传学。与此同时，DNA 测序技术的巨大进步使得在人群中测量和分析罕见变异成为可能。本综述考虑了这两个方面以及它们是如何结合在一起的。我们首先回顾 GWAS 和测序的历史。然后，我们考虑如何理解在没有罕见变异研究的情况下驱动强关联信号的生物学机制。我们描述了罕见变异研究如何补充这些方法，并强调了它们解释中的数据生成和统计挑战。最后，我们考虑了某些特殊的研究设计，例如针对家庭和隔离人群的设计，如何适应这一范式。
