Mapping the 17q12–21.1 locus for variants associated with early-onset Asthma in African Americans

Hongsheng Gui, Albert M. Levin, Donglei Hu, Patrick Sleiman, Shujie Xiao, Angel C.Y. Mak, Mao Yang, Andrea J. Barczak, Scott Huntsman, Celeste Eng, Samantha Hochstadt, Ellen Zhang, Kyle Whitehouse, Samantha Simons, Whitney Cabral, Sami Takriti, Gonçalo Abecasis, Thomas W. Blackwell, Hyun Min Kang, Deborah A. NickersonSoren Germer, David E. Lanfear, Frank Gilliland, W. James Gauderman, Rajesh Kumar, David J. Erle, Fernando D. Martinez, Hakon Hakonarson, Esteban G. Burchard, L. Keoki Williams

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)424-436
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume203
Issue number4
DOIs
StatePublished - Feb 15 2021

Keywords

  • African Americans
  • Asthma
  • Chromosome 17
  • GSDMB
  • ORMDL3

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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