Genome-wide interaction studies reveal sex-specific asthma risk alleles

Abstract

Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.

Figure 1.

The male-specific asthma association on 5q31.1 in European Americans. (A) The −log 10(P-value) is shown on the y-axis and position along chromosome 5q31.1 is shown on the x-axis. SNPs are shaded according to LD with the most significant SNP, rs2549003. This figure was generated using SNAP (27,28). (B) The log OR and 95% confidence interval for each of the EVE samples and in the combined sample. The black boxes are scaled by the standard error (larger boxes correspond to smaller error). (C) The association model with RAF for rs2549003 plotted separately in cases and controls and in males (solid line) and females (dashed line); the vertical bars represent the 95% confidence interval of the RAF.

Figure 2.

SLC22A4 gene expression by sex. Gene expression of SLC22A4, in units of log2 (intensity), plotted by sex (F = female, M = male) in whole blood samples from (A) CAMP, (B) CHS and (C) MCCAS.