Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations
NATURE GENETICS
Authors: Torgerson, Dara G.; Ampleford, Elizabeth J.; Chiu, Grace Y.; Gauderman, W. James; Gignoux, Christopher R.; Graves, Penelope E.; Himes, Blanca E.; Levin, Albert M.; Mathias, Rasika A.; Hancock, Dana B.; Baurley, James W.; Eng, Celeste; Stern, Debra A.; Celedon, Juan C.; Rafaels, Nicholas; Capurso, Daniel; Conti, David V.; Roth, Lindsey A.; Soto-Quiros, Manuel; Togias, Alkis; Li, Xingnan; Myers, Rachel A.; Romieu, Isabelle; Van Den Berg, David J.; Hu, Donglei; Hansel, Nadia N.; Hernandez, Ryan D.; Israel, Elliott; Salam, Muhammad T.; Galanter, Joshua; Avila, Pedro C.; Avila, Lydiana; Rodriquez-Santana, Jose R.; Chapela, Rocio; Rodriguez-Cintron, William; Diette, Gregory B.; Adkinson, N. Franklin; Abel, Rebekah A.; Ross, Kevin D.; Shi, Min; Faruque, Mezbah U.; Dunston, Georgia M.; Watson, Harold R.; Mantese, Vito J.; Ezurum, Serpil C.; Liang, Liming; Ruczinski, Ingo; Ford, Jean G.; Huntsman, Scott; Chung, Kian Fan; Vora, Hita; Li, Xia; Calhoun, William J.; Castro, Mario; Sienra-Monge, Juan J.; del Rio-Navarro, Blanca; Deichmann, Klaus A.; Heinzmann, Andrea; Wenzel, Sally E.; Busse, William W.; Gern, James E.; Lemanske, Robert F., Jr.; Beaty, Terri H.; Bleecker, Eugene R.; Raby, Benjamin A.; Meyers, Deborah A.; London, Stephanie J.; Gilliland, Frank D.; Burchard, Esteban G.; Martinez, Fernando D.; Weiss, Scott T.; Williams, L. Keoki; Barnes, Kathleen C.; Ober, Carole; Nicolae, Dan L.
Abstract
Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 x 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
Exome Analysis of Patients with Concurrent Pediatric Inflammatory Bowel Disease and Autoimmune Disease
INFLAMMATORY BOWEL DISEASES
Authors: Andreoletti, Gaia; Ashton, James J.; Coelho, Tracy; Willis, Claire; Haggarty, Rachel; Gibson, Jane; Holloway, John; Batra, Akshay; Afzal, Nadeem A.; Beattie, Robert Mark; Ennis, Sarah
Abstract
Background:Pediatric Inflammatory Bowel Disease (PIBD) is a chronic condition seen in genetically predisposed individuals. Genome-wide association studies have implicated >160 genomic loci in IBD with many genes coding for proteins in key immune pathways. This study looks at autoimmune disease burden in patients diagnosed with PIBD and interrogates exome data of a subset of patients.Methods:Patients were recruited from the Southampton Genetics of PIBD cohort. Clinical diagnosis of autoimmune disease in these individuals was ascertained from medical records. For a subset of patients with PIBD and concurrent asthma, exome data was interrogated to ascertain the burden of pathogenic variants within genes implicated in asthma. Association testing was conducted between cases and population controls using the SKAT-O test.Results:Forty-nine (28.3%) PIBD children (18.49% CD, 8.6% UC, and 21.15% IBDU patients) had a concurrent clinical diagnosis of at least one other autoimmune disorder; asthma was the most prevalent, affecting 16.2% of the PIBD cohort. Rare and common variant association testing revealed 6 significant genes (P < 0.05) before Bonferroni adjustment. Three of these genes were previously implicated in both asthma and IBD (ZPBP2 IL1R1, and IL18R1) and 3 in asthma only (PYHIN1, IL2RB, and GSTP1).Conclusions:One-third of our cohort had a concurrent autoimmune condition. We observed higher incidence of asthma compared with the overall pediatric prevalence. Despite a small sample size, SKAT-O evaluated a significant burden of rare and common mutations in 6 genes. Variant burden suggests that a systemic immune dysregulation rather than organ-specific could underpin immune dysfunction for a subset of patients.
COA
Publication 
Loading ......
