Admixture mapping of total serum IgE in African American subjects from CAAPA.

RATIONALE: Asthmatics of African descent have more severe asthma and higher total serum IgE (tIgE) levels compared to asthmatics of European ancestry. Admixture mapping is a powerful technique that leverages local ancestry to identify regions of the genome in admixed subjects where ancestry inherited from a particular ancestral population is associated with the phenotype of interest. Admixture mapping has not yet been used to map genetic loci influencing tIgE levels in African Americans. METHODS: Local ancestry was estimated using RFMix. The analysis was then stratified by asthma case-control status and the originating study (5 studies from CAAPA, the Consortium on Asthma among Africanancestry Populations in the Americas) with 1,182 cases and 816 controls in total. Linear mixed effect models were used to test for association between the number of copies of African ancestry at each local ancestry segment and Studentized residuals of log10 transformed tIgE (adjusted for age and sex). Association test statistics from the stratified analysis were combined in an inverse-variance meta-analysis. RESULTS: African ancestry was negatively correlated with tIgE at 8 local ancestry segments on chromosome 10p13-12.2, spanning 1,466,445 base pairs (P\u3c1.9e-4, correcting for 262 independent tests). The CUBN gene in this region plays a role in Vitamin B12 absorption and is the only gene found in the peak segment (hg19 positions 16,948,177-17,055,370). It has been hypothesized Vitamin B12 deficiency plays a role in both asthma and atopic disease. CONCLUSIONS: Our results suggest the CUBN gene affects tIgE levels in African Americans. Future work will include replication and finemapping

Admixture mapping of total serum IgE in African American subjects from CAAPA.

RATIONALE: Asthmatics of African descent have more severe asthma and higher total serum IgE (tIgE) levels compared to asthmatics of European ancestry. Admixture mapping is a powerful technique that leverages local ancestry to identify regions of the genome in admixed subjects where ancestry inherited from a particular ancestral population is associated with the phenotype of interest. Admixture mapping has not yet been used to map genetic loci influencing tIgE levels in African Americans. METHODS: Local ancestry was estimated using RFMix. The analysis was then stratified by asthma case-control status and the originating study (5 studies from CAAPA, the Consortium on Asthma among Africanancestry Populations in the Americas) with 1,182 cases and 816 controls in total. Linear mixed effect models were used to test for association between the number of copies of African ancestry at each local ancestry segment and Studentized residuals of log10 transformed tIgE (adjusted for age and sex). Association test statistics from the stratified analysis were combined in an inverse-variance meta-analysis. RESULTS: African ancestry was negatively correlated with tIgE at 8 local ancestry segments on chromosome 10p13-12.2, spanning 1,466,445 base pairs (P\u3c1.9e-4, correcting for 262 independent tests). The CUBN gene in this region plays a role in Vitamin B12 absorption and is the only gene found in the peak segment (hg19 positions 16,948,177-17,055,370). It has been hypothesized Vitamin B12 deficiency plays a role in both asthma and atopic disease. CONCLUSIONS: Our results suggest the CUBN gene affects tIgE levels in African Americans. Future work will include replication and finemapping

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%

Appendicitis risk prediction models in children presenting with right iliac fossa pain (RIFT study): a prospective, multicentre validation study.

Background Acute appendicitis is the most common surgical emergency in children. Differentiation of acute appendicitis from conditions that do not require operative management can be challenging in children. This study aimed to identify the optimum risk prediction model to stratify acute appendicitis risk in children. Methods We did a rapid review to identify acute appendicitis risk prediction models. A prospective, multicentre cohort study was then done to evaluate performance of these models. Children (aged 5\u201315 years) presenting with acute right iliac fossa pain in the UK and Ireland were included. For each model, score cutoff thresholds were systematically varied to identify the best achievable specificity while maintaining a failure rate (ie, proportion of patients identified as low risk who had acute appendicitis) less than 5%. The normal appendicectomy rate was the proportion of resected appendixes found to be normal on histopathological examination. Findings 15 risk prediction models were identified that could be assessed. The cohort study enrolled 1827 children from 139 centres, of whom 630 (34\ub75%) underwent appendicectomy. The normal appendicectomy rate was 15\ub79% (100 of 630 patients). The Shera score was the best performing model, with an area under the curve of 0\ub784 (95% CI 0\ub782\u20130\ub786). Applying score cutoffs of 3 points or lower for children aged 5\u201310 years and girls aged 11\u201315 years, and 2 points or lower for boys aged 11\u201315 years, the failure rate was 3\ub73% (95% CI 2\ub70\u20135\ub72; 18 of 539 patients), specificity was 44\ub73% (95% CI 41\ub74\u201347\ub72; 521 of 1176), and positive predictive value was 41\ub74% (38\ub75\u201344\ub74; 463 of 1118). Positive predictive value for the Shera score with a cutoff of 6 points or lower (72\ub76%, 67\ub74\u201377\ub74) was similar to that of ultrasound scan (75\ub70%, 65\ub73\u201383\ub71). Interpretation The Shera score has the potential to identify a large group of children at low risk of acute appendicitis who could be considered for early discharge. Risk scoring does not identify children who should proceed directly to surgery. Medium-risk and high-risk children should undergo routine preoperative ultrasound imaging by operators trained to assess for acute appendicitis, and MRI or low-dose CT if uncertainty remains. Funding None

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Abstract Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids