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

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.

Keywords: crohns disease; inflammatory bowel disease; rare variants; statistical genetics; ulcerative colitis.

Figure 1

Variant effect sizes for IBD (7, 42, 43). x-axis represents MAF of variant. y-axis represents the log (OR) for the maximum of IBD, CD or UC effects for each variant.

Figure 2

Power to detect PTV associations in PCSK9 across multiple populations using a 25 000 cases by 25 000 controls study design (76). The assumed prevalence, heterozygous relative risk and type 1 error rate are as specified in the sidebar. x-axis indicates gnomAD population (AFR, African; AMR, Native American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; NFE, Non-Finnish European; SAS, South Asian; UKB, UK Biobank). y-axis reflects power to detect. Point estimates are plotted alongside 95% confidence intervals. Composite PTV allele frequency is obtained by summing allele counts for all high-confidence PTVs in the gene per population.