Further replication studies of the EVE Consortium meta-analysis identifies 2 asthma risk loci in European Americans

Abstract

Background: Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk.

Objectives: We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis.

Methods: We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis.

Results: Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos.

Conclusions: This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations.

Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Figures

Figure 1

Q-Q plots of the replication results. In each plot (A–D), the observed -log(p-value) is plotted against the expected -log(p-value). A) The 128 SNPs selected for replication in the European American samples, B) 340 SNPs selected for replication in the African Americans, C), 258 SNPs selected for replication in the Latinos, and D) 2450 SNPs selected for replication in all samples.

Figure 2

Results for rs1061477 in the KLK3 gene. A) Forest plot showing the odds ratios (OR) and 95% confidence intervals for all European American studies in the primary and replication meta-analyses. Two European American studies included in the primary analysis (CARE and CAMP) were family-based studies and did not report odds ratios; those studies are not included in the figure. The R package meta was used for determining the combined OR andrmeta was used to generate the plot. B) Regional plot of the European American association p-values surrounding rs1061477. Diamond represents p-values for SNPs from the primary study and circles represent the combined (primary + replication) p-values. SNPs are shaded according to LD with the SNP rs1061477, red indicating high LD. The light blue line represents CEU 1000 genomes pilot recombination rates. This figure was generated using SNAP (35, 36).

Figure 3

Results for rs9570077 on 13q21. A) Forest plot showing the odds ratios (OR) and 95% confidence intervals for all European American studies in the primary and replication meta-analyses. Two European American studies included in the primary analysis (CARE and CAMP) were family-based studies and did not report odds ratios; those studies are not included in the figure. The R package meta was used for determining the combined OR andrmeta was used to generate the plot. B) Regional plot of the European American association p-values surrounding rs9570077. Diamond represents p-values for SNPs from the primary study and circles represent the combined (primary + replication) p-values. SNPs are shaded according to LD with the SNP rs9570077, red indicating high LD. The light blue line represents CEU 1000 genomes pilot recombination rates. This figure was generated using SNAP (35, 36).

Figure 4

Forest plot of rs9891949 near AURKB. The odds ratios (OR) and 95% confidence intervals for all European American studies in the primary and replication meta-analyses. Two European American studies included in the primary analysis (CARE and CAMP) were family-based studies and did not report odds ratios; those studies are not included in the figure.