Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

Global Sensory Impairment Predicts Morbidity and Mortality in Older U.S. Adults.

OBJECTIVES: To evaluate global sensory impairment (GSI, an integrated measure of sensory dysfunction) as a predictor of physical function, cognition, overall health, and mortality. DESIGN: Prospective study. SETTING: The National Social Life, Health, and Aging Project. PARTICIPANTS: A national probability sample of 3,005 home-dwelling older U.S. adults assessed at baseline (2005-06) and 5-year follow-up (2010-11). MEASUREMENTS: Gait speed, activity, disability, cognition, overall health, 5-year mortality. RESULTS: At baseline, older adults with worse GSI were slower (Timed Up and Go times: odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.17-1.50) and had more activity of daily living deficits (≥2: OR = 1.26, 95% CI = 1.10-1.46). Five years later, they were still slower (timed walk: OR = 1.22, 95% CI = 1.05-1.42), had more disabilities (≥2 instrumental activities of daily living; OR = 1.45, 95% CI = 1.23-1.70), were less active (daytime activity according to accelerometry: ß = -2.7, 95% CI = -5.2 to -0.2), had worse cognitive function (Montreal Cognitive Assessment; ß = -0.64, 95% CI = -0.84 to -0.44), more likely to have poorer overall health (OR = 1.16, 95% CI = 1.03-1.31) and lose weight (>10%: OR = 1.31, 95% CI = 1.04-1.64), and have died (OR = 1.45, 95% CI = 1.19-1.76). All analyses were adjusted for relevant confounders at baseline, including age, sex, race and ethnicity, education, smoking, problem drinking, body mass index, comorbidities, and cognitive function. CONCLUSION: GSI predicts impaired physical function, cognitive dysfunction, significant weight loss, and mortality 5 years later in older U.S. adults. Multisensory evaluation may identify vulnerable individuals, offering the opportunity for early intervention to mitigate adverse outcomes.