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Hum Mol Genet. 2019 Jul 31. pii: ddz189. doi: 10.1093/hmg/ddz189. [Epub ahead of print]

Rare and common variant discovery in complex disease: the IBD case study.

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Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA.


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.


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