Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA.
Hum Mol Genet. 2019 Nov 21;28(R2):R162-R169. doi: 10.1093/hmg/ddz189.
Complex diseases such as inflammatory bowel disease (IBD), which consists of ulcerative colitis and Crohn's disease, are a significant medical burden-70 000 new cases of IBD are diagnosed in the United States annually. In this review, we examine the history of genetic variant discovery in complex disease with a focus on IBD. We cover methods that have been applied to microsatellite, common variant, targeted resequencing and whole-exome and -genome data, specifically focusing on the progression of technologies towards rare-variant discovery. The inception of these methods combined with better availability of population level variation data has led to rapid discovery of IBD-causative and/or -associated variants at over 200 loci; over time, these methods have grown exponentially in both power and ascertainment to detect rare variation. We highlight rare-variant discoveries critical to the elucidation of the pathogenesis of IBD, including those in NOD2, IL23R, CARD9, RNF186 and ADCY7. We additionally identify the major areas of rare-variant discovery that will evolve in the coming years. A better understanding of the genetic basis of IBD and other complex diseases will lead to improved diagnosis, prognosis, treatment and surveillance.
复杂疾病，如炎症性肠病（IBD），包括溃疡性结肠炎和克罗恩病，是一个重大的医疗负担——美国每年诊断出 7 万例新的 IBD 病例。在这篇综述中，我们考察了复杂疾病中遗传变异发现的历史，重点是 IBD。我们涵盖了已应用于微卫星、常见变异、靶向重测序以及全外显子和全基因组数据的方法，特别关注了向稀有变异发现发展的技术进展。这些方法的出现，加上人群水平变异数据的更好可用性，导致了在 200 多个位点上迅速发现 IBD 致病和/或相关变异；随着时间的推移，这些方法在检测稀有变异的能力和确定程度上都呈指数级增长。我们强调了对 IBD 发病机制阐明至关重要的稀有变异发现，包括 NOD2、IL23R、CARD9、RNF186 和 ADCY7 中的发现。我们还确定了未来几年将发展的稀有变异发现的主要领域。对 IBD 和其他复杂疾病遗传基础的更好理解将导致改善诊断、预后、治疗和监测。
