Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in mexican children

Abstract

Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case-parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10x10(-6) in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79x10(-7)). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma.

Figure 1. Quantile-quantile plot.

Observed log-linear p-values (black dots) and the corresponding expected log-linear p-values (red line) are plotted on the logarithmic scale for the 520,767 autosomal GWAS SNPs tested for association with childhood asthma.

Figure 2. Physical location of GWAS p-values.

Observed log-linear p-values on the logarithmic scale are sorted by physical location on the 22 autosomes for the 520,767 SNPs tested for association with childhood asthma. The 11 of the top 18 SNPs selected for replication are located at or above the solid line (p≤3.3×10⁻⁵).

Figure 3. Chromosome 9q21.31 ancestry analysis.

Segregation of Native American ancestry was tested along chromosome 9q21.31, the chromosomal region containing the replicated SNP (rs2378383). A 2,000 SNP window surrounding rs2378383 (located at the vertical blue line) is shown. Data points in red show a significant under- (or over-) transmission of Native American ancestry with |z-score| greater than 1.96, corresponding to an uncorrected p-value of 0.05.

Figure 4. GWAS findings in the context of genome-wide expression.

Genome-wide expression profiles were obtained from publicly available Novartis Research Foundation data, and the gene expression patterns were examined in the context of GWAS results for 14,330 genes. P-values for the Wilcoxon rank-sum test on the logarithmic scale indicate the significance in the difference of median GWAS q-values in genes expressed versus genes not expressed in each of 51 human tissues. Significance thresholds of p<0.01 (solid line) and p<0.05 (dashed line) are shown.