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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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1
Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA.

Abstract

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.

PMID:
31363759
DOI:
10.1093/hmg/ddz189

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