Hongsheng Gui1, Albert M Levin2, Donglei Hu3, Patrick Sleiman4,5, Shujie Xiao1, Angel C Y Mak3, Mao Yang1, Andrea J Barczak6,7, Scott Huntsman3, Celeste Eng3, Samantha Hochstadt1, Ellen Zhang1, Kyle Whitehouse1, Samantha Simons1, Whitney Cabral1, Sami Takriti1, Gonçalo Abecasis8, Thomas W Blackwell8, Hyun Min Kang8, Deborah A Nickerson9,10,11, Soren Germer12, David E Lanfear1, Frank Gilliland13, W James Gauderman13, Rajesh Kumar14, David J Erle3,6,7, Fernando D Martinez15,16, Hakon Hakonarson4,5, Esteban G Burchard3,17, L Keoki Williams1. 1. Department of Internal Medicine, Center for Individualized and Genomic Medicine Research and. 2. Department of Public Health Sciences, Henry Ford Health System, Detroit, Michigan. 3. Department of Medicine. 4. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 5. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 6. Lung Biology Center. 7. CoLabs, and. 8. Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan. 9. Department of Genome Sciences, University of Washington, Seattle, Washington. 10. Northwest Genomics Center, Seattle, Washington. 11. Brotman Baty Institute, Seattle, Washington. 12. New York Genome Center, New York, New York. 13. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. 14. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and. 15. Arizona Respiratory Center and. 16. Department of Pediatrics, University of Arizona, Tucson, Arizona. 17. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California.
Abstract
Rationale: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants. Objectives: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals. Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant.Measurements and Main Results: The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.
Rationale: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants. Objectives: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals. Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant.Measurements and Main Results: The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.
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