Unifying candidate gene and GWAS Approaches in Asthma

PLoS One. 2010 Nov 12;5(11):e13894. doi: 10.1371/journal.pone.0013894.

Abstract

The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values <0.0035 (corrected for multiple testing). Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p = 0.05 and p = 0.0035. These data indicate that (a) GWAS coverage is insufficient for many asthma candidate genes, (b) imputation based on these data is reliable but incomplete, and (c) SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Asthma / genetics*
  • Child
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • Endothelin-1 / genetics
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods*
  • Genotype
  • Glutathione S-Transferase pi / genetics
  • Humans
  • Interleukin-12 Subunit p40 / genetics
  • Interleukin-13 / genetics
  • Interleukin-4 / genetics
  • Interleukin-4 Receptor alpha Subunit / genetics
  • Male
  • Membrane Proteins / genetics
  • Polymorphism, Single Nucleotide*
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Endothelin-1
  • IL12B protein, human
  • IL4R protein, human
  • Interleukin-12 Subunit p40
  • Interleukin-13
  • Interleukin-4 Receptor alpha Subunit
  • Membrane Proteins
  • ORMDL3 protein, human
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • GSTP1 protein, human
  • Glutathione S-Transferase pi
  • DPP10 protein, human
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases