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Multicenter Study
. 2014 Aug;134(2):295-305.
doi: 10.1016/j.jaci.2013.08.055. Epub 2014 Jan 7.

Genome-wide association study and admixture mapping identify different asthma-associated loci in Latinos: the Genes-environments & Admixture in Latino Americans study

Joshua M Galanter  1 , Christopher R Gignoux  2 , Dara G Torgerson  3 , Lindsey A Roth  3 , Celeste Eng  3 , Sam S Oh  3 , Elizabeth A Nguyen  4 , Katherine A Drake  2 , Scott Huntsman  3 , Donglei Hu  3 , Saunak Sen  5 , Adam Davis  6 , Harold J Farber  7 , Pedro C Avila  8 , Emerita Brigino-Buenaventura  9 , Michael A LeNoir  10 , Kelley Meade  6 , Denise Serebrisky  11 , Luisa N Borrell  12 , William Rodríguez-Cintrón  13 , Andres Moreno Estrada  14 , Karla Sandoval Mendoza  14 , Cheryl A Winkler  15 , William Klitz  16 , Isabelle Romieu  17 , Stephanie J London  18 , Frank Gilliland  19 , Fernando Martinez  20 , Carlos Bustamante  14 , L Keoki Williams  21 , Rajesh Kumar  22 , José R Rodríguez-Santana  23 , Esteban G Burchard  24
Affiliations
Multicenter Study

Genome-wide association study and admixture mapping identify different asthma-associated loci in Latinos: the Genes-environments & Admixture in Latino Americans study

Joshua M Galanter et al. J Allergy Clin Immunol. 2014 Aug.

Abstract

Background: Asthma is a complex disease with both genetic and environmental causes. Genome-wide association studies of asthma have mostly involved European populations, and replication of positive associations has been inconsistent.

Objective: We sought to identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping.

Methods: Latino children with asthma (n = 1893) and healthy control subjects (n = 1881) were recruited from 5 sites in the United States: Puerto Rico, New York, Chicago, Houston, and the San Francisco Bay Area. Subjects were genotyped on an Affymetrix World Array IV chip. We performed genome-wide association and admixture mapping to identify asthma-associated loci.

Results: We identified a significant association between ancestry and asthma at 6p21 (lowest P value: rs2523924, P < 5 × 10(-6)). This association replicates in a meta-analysis of the EVE Asthma Consortium (P = .01). Fine mapping of the region in this study and the EVE Asthma Consortium suggests an association between PSORS1C1 and asthma. We confirmed the strong allelic association between SNPs in the 17q21 region and asthma in Latinos (IKZF3, lowest P value: rs90792, odds ratio, 0.67; 95% CI, 0.61-0.75; P = 6 × 10(-13)) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies.

Conclusions: Admixture mapping and genome-wide association are complementary techniques that provide evidence for multiple asthma-associated loci in Latinos. Admixture mapping identifies a novel locus on 6p21 that replicates in a meta-analysis of several Latino populations, whereas genome-wide association confirms the previously identified locus on 17q21.

Keywords: 17q21; 6p21; Asthma; Latinos; admixture mapping; genome-wide association study; local ancestry.

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Figures

Figure 1
Figure 1
Proportions of individual Native American, European, and African ancestry in the GALA II participants. Each bar represents one individual. There is substantial variability in individual ancestry both within and between Latino ethnic sub-groups.
Figure 2
Figure 2
Admixture mapping results. A. Manhattan plot of the admixture mapping study, showing a significant peak in chromosome 6. The red line represents the fifth percentile of the lowest p3 value in 10,000 permutations. B. Locus-zoom plot of the admixture mapping peak, which is centered in the MUC21 and MUC22 gene cluster, upstream of HLA-B and HLA-C genes.
Figure 3
Figure 3
Forest plot of the meta-analysis of the effect of Native American ancestry on asthma in the Latino studies within the EVE consortium. The odds ratio and [95% confidence interval] are listed next to each study.
Figure 4
Figure 4
Genome-wide association study results. A. Manhattan plot of the GWAS, showing a genome-wide significant peak at chromosome 17q21. B. Locus-zoom plot of the 17q21 peak, which shows a broad area of linkage disequilibrium, with the most significant finding centered on the IKZF3 gene.
Figure 5
Figure 5
Replication of previous genome-wide findings in the GALA II study. When provided, the original study's effect estimate and confidence interval are given in red, while the effect estimate and confidence interval in the present study are shown in teal. One study, including three SNPs reported only a summary p-value.(10) A second study, including one SNP, reported an odds ratio, but not confidence interval.(56) + Replication was in the same direction as the original study. 3 Replication was in the opposite direction as the original study. ? The direction of replication could not be assessed. MHC major histocompatibility complex region.
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