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. 2015 Jul;106(1):15-22.
doi: 10.1016/j.ygeno.2015.03.003. Epub 2015 Mar 25.

Genomic architecture of asthma differs by sex

Tesfaye B Mersha  1 , Lisa J Martin  2 , Jocelyn M Biagini Myers  3 , Melinda Butsch Kovacic  4 , Hua He  5 , Mark Lindsey  6 , Umasundari Sivaprasad  7 , Weiguo Chen  8 , Gurjit K Khurana Hershey  9
Affiliations

Genomic architecture of asthma differs by sex

Tesfaye B Mersha et al. Genomics. 2015 Jul.

Abstract

Asthma comprised of highly heterogeneous subphenotypes resulting from complex interplay between genetic and environmental stimuli. While much focus has been placed on extrinsic environmental stimuli, intrinsic environment such as sex can interact with genes to influence asthma risk. However, few studies have examined sex-specific genetic effects. The overall objective of this study was to evaluate if sex-based differences exist in genomic associations with asthma. We tested 411 asthmatics and 297 controls for presence of interactions and sex-stratified effects in 51 genes using both SNP and gene expression data. Logistic regression was used to test for association. Over half (55%) of the genetic variants identified in sex-specific analyses were not identified in the sex-combined analysis. Further, sex-stratified genetic analyses identified associations with significantly higher median effect sizes than sex-combined analysis for girls (p-value=6.5E-15) and for boys (p-value=1.0E-7). When gene expression data were analyzed to identify genes that were differentially expressed in asthma versus non-asthma, nearly one third (31%) of the probes identified in the sex-specific analyses were not identified in the sex-combined analysis. Both genetic and gene expression data suggest that the biologic underpinnings for asthma may differ by sex. Failure to recognize sex interactions in asthma greatly decreases the ability to detect significant genomic variation and may result in significant misrepresentation of genes and pathways important in asthma in different environments.

Keywords: Asthma; Expression–Sex interaction; Gene–Sex interaction; Sex-stratified analysis.

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Figures

Figure 1
Figure 1. Sex-Combined and Sex-Stratified Analyses Identify Unique Asthma-Associated SNPs
Logistic regression was performed adjusting for sex, age and population stratification. Odds Ratios of asthma are shown on the y-axis. The x-axis represents the candidate SNPs genotyped across the candidate genes studied. (a) Sex-combined results (boys and girls together). (b) and (c) Sex-stratified results (only girls and boys, respectively). The horizontal dotted line represents the level at which we are sufficiently powered to detect effect sizes greater than 1.44 in the sex-combined analysis. (d) The median odds ratios in both the sex-combined and sex-stratified analyses.
Figure 2
Figure 2. Sex-specific analyses account for a substantial proportion of the detected associations
The bars represent the cumulative frequency of identified SNPs and probes with nominal association from either the sex-combined or sex-specific analyses.
Figure 3
Figure 3. SNPs and Probes with Sex Stratified Effects and Interaction Are Difficult to Detect in Combined Analysis
Among all SNPs and Probes identified as nominally associated in sex-stratified and interaction analyses, what proportion are also nominally associated in the sex-combined analyses (p-value <0.05). Black bars represent SNPs and probes with no interaction effect, grey bars represent SNPs and probes with nominal interaction effects .
Figure 4
Figure 4. Sex-Combined and Sex-Stratified Analyses Identify Unique Asthma-Associated Expression Profiles
Logistic regression was performed adjusting for sex, age and population stratification. Beta values are shown on the y-axis. The x-axis represents the candidate probe across the candidate genes studied. (a) Sex-combined results (boys and girls together). (b) and (c) Sex-stratified results (only girls and boys, respectively). The horizontal dotted line represents the level at which we are sufficiently powered to detect effect sizes greater than 0.90 in the sex-combined analysis. (d) The median odds ratios in both the sex-combined and sex-stratified analyses.
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