A genome-wide association study to identify genetic determinants of atopy in subjects from the United Kingdom

Abstract

A genetic component in the development of atopy has been identified. However, numerous heritability models have been proposed with inconsistent replication of susceptibility loci and genes. We sought to use a genome-wide association study approach to examine genetic susceptibility to atopy, which was defined as increased specific IgE levels, positive skin prick test (SPT) responses, or both, within a large discovery cohort and 3 additional white populations. Single nucleotide polymorphisms (SNPs) across the genome were tested for association with increased specific IgE levels (≥ 0.35 kU(A)/L) in the British 1958 Birth Cohort (1083 cases and 2770 control subjects; Illumina 550K Array) to 1 or more allergens, including house dust mite (Der p 1), mixed grass, or cat fur. Independent replication of identified loci (P ≤ .05) was assessed in 3 case-control cohorts from the United Kingdom (n = 3225). Combined analyses of data for top signals across cohorts were conducted for atopic phenotypes: increased specific IgE levels (1378 cases and 3151 control subjects) and positive SPT responses (1058 cases and 2167 control subjects). A single SNP on chromosome 13q14 met genome-wide significance (P = 2.15 × 10(-9)), and a further 6 loci (4.50 × 10(-7) ≤ P ≤ 5.00 × 10(-5)) showed weaker evidence for association with increased specific IgE levels in the British 1958 Birth Cohort. However, no SNPs studied showed consistent association with atopy defined by increased specific IgE levels, positive SPT responses, or both in all study cohorts. Seven putative atopy loci were identified using a genome-wide association study approach but showed limited replication across several white populations. This study suggests that large-scale analyses with results from multiple populations will be needed to reliably identify key genetic factors underlying atopy predisposition.