Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients.

Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

Effects of driving distance and transport time on mortality among Level I and II traumas occurring in a metropolitan area.

BACKGROUND: The purpose of this study was to evaluate the effects of ambulance driving distance and transport time on mortality among trauma incidents occurring in the City of Chicago, a large metropolitan area. METHODS: We studied individuals 16 years or older who suffered a Level I or II injury and were taken to a Level I trauma center. The outcome was in-hospital mortality, including those dead on arrival but excluding those deemed dead on scene. Driving distance was calculated from the scene of injury to the trauma center where the patient was taken. Transport time was defined as the time from scene departure to arrival at the trauma center. Covariates included injury severity measures recorded at the scene. Logistic regression and instrumental variable probit regression models were used to examine the association between driving distance, transport time, and mortality, adjusting for injury severity. RESULTS: A total of 24,834 incidents were analyzed, including 1,464 deaths. Median driving distance was 3.9 miles, and median transport time was 13 minutes. Our findings indicate that increased driving distance is associated with a modest increase in mortality, with a covariate-adjusted odds ratio of 1.12 per 2-mile increase in distance (95% confidence interval [CI], 1.05-1.20). This corresponds to an increase in overall mortality of 0.26 percentage points per 2 miles (95% CI, 0.11-0.40). Using distance as an instrumental variable, we estimate a 0.51 percentage point increase in mortality per 5-minute increase in transport time (95% CI, 0.14-0.89). CONCLUSION: We find a modest effect of distance on mortality that is approximately linear over a range of 0 to 12 miles. Instrumental variables analysis indicated a corresponding increase in mortality with increasing transport time. Limitations of the study include the possibility of unmeasured confounders and the assumption that distance affects mortality only through its effect on transport time. LEVEL OF EVIDENCE: Prognostic study, level III.

Assessment of sleep in the National Social Life, Health, and Aging Project.

OBJECTIVES: The relationship of sleep to health has been an active area of research in recent years, and the National Social Life, Health, and Aging Project (NSHAP) expanded sleep data collection in Wave 2 with enhanced core questions and a novel sleep module that included an objective measure of sleep duration and quality. METHOD: A randomly selected one-third of Wave 2 participants and their spouses or coresident partners were invited to participate in the sleep module. Objective sleep data were collected using wrist actigraphy, an accelerometer that records an integrated measure of motion over short epochs (15 s each). This information is stored and subsequently analyzed to determine sleep and wake periods by epoch. Individuals were instructed to wear the actiwatches for 72 hr. Several sleep parameters were derived from the accelerometer. Individuals concurrently kept a sleep diary. RESULTS: Sleep actigraphy data were successfully collected from 780 individuals. Many of the survey-based and the actigraph-estimated sleep parameters varied by age and gender. However, age and gender patterns often differed for sleep characteristics that were both asked and measured, such as sleep duration. DISCUSSION: The survey and actigraphy data provide different information about sleep characteristics. The opportunity to examine actigraph-estimated sleep characteristics in a nationally representative sample of older adults allows novel analyses of the associations of sleep parameters with social and health data.

Refined genomic localization and ethnic differences observed for the IBD5 association with Crohn's disease.

Although the general association of the inflammatory bowel disease (IBD) 5 region on chromosome 5q31 to Crohn's disease (CD) has been replicated repeatedly, the identity of the precise causal variant within the region remains unknown. A recent report proposed polymorphisms in solute carrier family 22, member 4 (SLC22A4) organic cation transporter 1(OCTN1) and solute carrier family 22, member 5 (SLC22A5) (OCTN2) as responsible for the IBD5 association, but definitive, large-sample comparison of those polymorphisms with others known to be in strong linkage disequilibrium was not performed. We evaluated 1879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for six IBD5 tag single nucleotide polymorphisms (SNPs) to evaluate association localization and ethnic and subphenotypic specificity. We confirm association to the IBD5 region (best SNP IGR2096a_1/rs12521868, P<0.0005) and show this association to be exclusive to the non-Jewish (NJ) population (P=0.00005) (risk allele undertransmitted in Ashkenazi Jews). Using Phase II HapMap data, we demonstrate that there are a set of polymorphisms, spanning genes from prolyl 4-hydroxylase (P4HA2) through interferon regulatory factor 1 (IRF1) with equivalent statistical evidence of association to the reported SLC22A4 variant and that each, by itself, could entirely explain the IBD5 association to CD. Additionally, the previously reported SLC22A5 SNP is rejected as the potential causal variant. No specificity of association was seen with respect to disease type and location, and a modest association to ulcerative colitis is also observed. We confirm the importance of IBD5 to CD susceptibility, demonstrate that the locus may play a role in NJ individuals only, and establish that IRF1, PDLIM, and P4HA2 may be equally as likely to contain the IBD5 causal variant as the OCTN genes.