Abstract
Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals1, partly because of a shared genetic origin2,3,4. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10−8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.
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Acknowledgements
This research was conducted using the UK Biobank resource under application number 10074. Detailed acknowledgments and funding details are provided for each contributing study in the Supplementary Note.
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Data collection and analysis in the contributing studies: M.A.F., M.C.M., S.C.D., L.M.B., P.J.T., N.G.M., D.L.D. (AAGC study); J.M.V., G.H.K. (LifeLines study); H.B., E.R., M.H., A.F., N.N., H.S., S.K., C.G., K.S., S.W. (GENEVA study); I.M., F.R., J.E.-G., S.G., A.A., G.H., C.O.S., N.H., Y.-A.L. (GENUFAD studies); C.T., D.A.H. (23andMe study); J.D.H., J.S.W., R.B.M., E.J. (GERA study); Q.H., J.-J.H., G.W., D.I.B. (NTR study); A.T., V.U., Y.L., P.K.E.M., C.A., R.K. (CATSS, TWINGENE and SALTY studies); L.P. (ALSPAC study); B.M.B., L.G.F., M.E.G., J.B.N., W.Z., K.H., A.L., O.L.H., M.L., G.R.A., C.J.W. (HUNT study); L.P., M.A.F. (UK Biobank study). Methylation analysis: J.v.D., D.I.B., R.J. Biological and drug annotation: M.A.F., C.W.M., E.M., K.B., O.H., J.Z., J.A.R., J.B., B.B. Quality control, meta-analysis, tables and figures: M.A.F. Writing group: M.A.F., J.M.V., I.M., C.T., J.D.H., Q.H., A.T., V.U., J.v.D., Y.L., J.E.-G., B.M.B., J.B., S.C.D., S.W., P.K.E.M., R.J., E.J., Y.-A.L., D.I.B., C.A., R.K., G.H.K., L.P. Study design and management: M.A.F., D.A.H., B.M.B., S.W., P.K.E.M., R.J., E.J., Y.-A.L., D.I.B., C.A., R.K., G.H.K., L.P.
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A full list of members and affiliations appears in the Supplementary Note.
A full list of members and affiliations appears in the Supplementary Note.
A full list of members and affiliations appears in the Supplementary Note.
A full list of members and affiliations appears in the Supplementary Note.
Integrated supplementary information
Supplementary Figure 1 Summary of main analyses and key findings.
Meta-analysis of GWAS results from 13 studies identified 136 variants independently associated with disease risk at a P < 3 × 10−8, of which 73 were in low LD (r2 < 0.05) with published allergy risk variants. Based on a high LD (r2 > 0.8) between the 136 sentinel risk variants and sentinel cis-eQTLs and/or nonsynonymous coding variants, a total of 132 likely target genes were identified. The likely target genes were preferentially expressed in whole blood and lung, and enriched among pathways related to lymphocyte immunity. Twenty-nine genes are targets of drugs considered for clinical development, including six for which the effect on gene expression of the allergy-protective allele and the respective drug matched. Thirty-six genes have a nearby CpG for which methylation levels are associated with gene expression levels independently of SNP effects on expression and methylation. For one of these genes, variation in methylation levels at the expression-associated CpG was significantly associated with smoking status.
Supplementary Figure 2 Distribution of the observed and expected association P values for the allergic disease GWAS performed in each individual study that contributed to the meta-analysis.
For each study, the genomic inflation factor (λ; estimated as the median χ2 divided by 0.4549) is also shown. The intercept of LD score regression for each study is shown in Supplementary Table 1.
Supplementary Figure 3 Eighty-nine allergy risk variants (gray bars) in low LD (r2 < 0.05) with each other reported in previous GWAS, according to the year each association was first reported.
We identified 185 SNP associations with allergic disease at P < 5 × 10−8 in the NHGRI-EBI GWAS catalog. Correlated SNPs were then grouped based on LD, such that the lead SNP in each group was in LD (r2 > 0.05) with other variants in that group but not with the lead SNPs of all other groups. This procedure is described in greater detail in the Supplementary Note. This resulted in 89 groups of SNPs associated with allergic disease. The earliest year an association was reported with a variant in each group was identified and plotted. The red bar shows the number of novel variants discovered in this study (50 in new loci and 23 in known loci).
Supplementary Figure 4 Twenty-six of the 136 sentinel variants were significantly associated with variation in the reported age of onset for allergic disease.
We first tested the association between each sentinel variant and the age at which symptoms of any allergic disease (asthma, hay fever or eczema) were first reported, using data from the UK Biobank study (n = 35,972). After correcting for multiple testing, 26 variants (yellow circles) had a significant association with age of onset with the allergy-predisposing allele always associated with decreased age of onset (i.e., a negative β, shown on the y axis). An additional 47 variants (blue circles) were nominally associated (P < 0.05) with age of onset. We then performed the same analysis separately for individuals who reported suffering only from a single disease and formally compared the SNP effects between the three groups. In these analyses, the effect on age of onset was significantly different (P < 0.05) between the three diseases for 8 of the 26 variants (yellow circles with black inner dot), consistent with the presence of disease-specific SNP effects on age of onset.
Supplementary Figure 5 Enrichment of tissue-specific gene expression in 25 broad tissues studied by the GTEx Consortium, after restricting the background gene list to the subset of genes with eQTLs.
We repeated the tissue-specific enrichment analysis described in Figure 3a after restricting the background gene list to the subset of 12,804 genes with a known eQTL. Random genes were also drawn from the subset with a known eQTL.
Supplementary Figure 6 Enrichment of SNP heritability among immune cell enhancers remains after excluding from the analysis the 136 sentinel variants.
We repeated the SNP heritability enrichment analysis described in Figure 3b after excluding the 136 sentinel variants (and all variants correlated at r2 > 0.05) from the meta-analysis results.
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Ferreira, M., Vonk, J., Baurecht, H. et al. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nat Genet 49, 1752–1757 (2017). https://doi.org/10.1038/ng.3985
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DOI: https://doi.org/10.1038/ng.3985
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