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 Seibold, Badri 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

Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. Perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. We leveraged the mixed ancestry of 3,902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3,774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of >500 individuals from 3 racial/ethnic groups. We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (p=6.8x10-6), where Native American ancestry was associated with increased risk of asthma (OR=1.20, 95% CI=1.07-1.34, p=0.002) and European ancestry with protection (OR=0.86, 95% CI=0.77-0.96, p=0.008). Our findings replicated in an independent childhood asthma study in Latinos (p=5.3x10-3, combined p=2.6x10-7). Fine mapping of 18q21 in 1,978 Latinos identified a significant association with multiple variants 5' of 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<0.001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. Ancestry at 18q21 was significantly associated with asthma in Latinos, and implicated multiple ancestry-informative non-coding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.