An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

Christopher R. Gignoux, Dara G. Torgerson, Maria Pino-Yanes, Lawrence H. Uricchio, Joshua Galanter, Lindsey A. Roth, Celeste Eng, Donglei Hu, Elizabeth A. Nguyen, Scott Huntsman, Rasika A. Mathias, Rajesh Kumar, Jose Rodriguez-Santana, Neeta Thakur, Sam S. Oh, Meghan McGarry, Andres Moreno-Estrada, Karla Sandoval, Cheryl A. Winkler, Max A. SeiboldBadri Padhukasahasram, David V. Conti, Harold J. Farber, Pedro Avila, Emerita Brigino-Buenaventura, Michael Lenoir, Kelley Meade, Denise Serebrisky, Luisa N. Borrell, William Rodriguez-Cintron, Shannon Thyne, Bonnie R. Joubert, Isabelle Romieu, Albert M. Levin, Juan Jose Sienra-Monge, Blanca Estela del Rio-Navarro, Weiniu Gan, Benjamin A. Raby, Scott T. Weiss, Eugene Bleecker, Deborah A. Meyers, Fernando J. Martinez, W. James Gauderman, Frank Gilliland, Stephanie J. London, Carlos D. Bustamante, Dan L. Nicolae, Carole Ober, Saunak Sen, Kathleen Barnes, L. Keoki Williams, Ryan D. Hernandez, Esteban G. Burchard

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Background: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. Objective: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. Methods: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. Results: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10 −6 ), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10 −3 , combined P = 2.6 × 10 −7 ). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5′ of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. Conclusion: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

Original languageEnglish (US)
Pages (from-to)957-969
Number of pages13
JournalJournal of Allergy and Clinical Immunology
Volume143
Issue number3
DOIs
Publication statusPublished - Mar 2019

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Keywords

  • admixture mapping
  • Asthma
  • asthma exacerbations
  • gene expression
  • Latinos
  • meta-analysis
  • rare variation
  • SMAD2
  • targeted sequencing

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Gignoux, C. R., Torgerson, D. G., Pino-Yanes, M., Uricchio, L. H., Galanter, J., Roth, L. A., ... Burchard, E. G. (2019). An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos. Journal of Allergy and Clinical Immunology, 143(3), 957-969. https://doi.org/10.1016/j.jaci.2016.08.057