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A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci

Abstract

Allergic disease is very common and carries substantial public-health burdens. We conducted a meta-analysis of genome-wide associations with self-reported cat, dust-mite and pollen allergies in 53,862 individuals. We used generalized estimating equations to model shared and allergy-specific genetic effects. We identified 16 shared susceptibility loci with association P < 5 × 10−8, including 8 loci previously associated with asthma, as well as 4p14 near TLR1, TLR6 and TLR10 (rs2101521, P = 5.3 × 10−21); 6p21.33 near HLA-C and MICA (rs9266772, P = 3.2 × 10−12); 5p13.1 near PTGER4 (rs7720838, P = 8.2 × 10−11); 2q33.1 in PLCL1 (rs10497813, P = 6.1 × 10−10), 3q28 in LPP (rs9860547, P = 1.2 × 10−9); 20q13.2 in NFATC2 (rs6021270, P = 6.9 × 10−9), 4q27 in ADAD1 (rs17388568, P = 3.9 × 10−8); and 14q21.1 near FOXA1 and TTC6 (rs1998359, P = 4.8 × 10−8). We identified one locus with substantial evidence of differences in effects across allergies at 6p21.32 in the class II human leukocyte antigen (HLA) region (rs17533090, P = 1.7 × 10−12), which was strongly associated with cat allergy. Our study sheds new light on the shared etiology of immune and autoimmune disease.

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Figure 1: Manhattan plot of meta-analysis results for shared effects.
Figure 2: Manhattan plot of meta-analysis results for interactions with allergen.
Figure 3: Marginal effect sizes and 95% confidence intervals for rs17533090 for cat, pollen and dust-mite allergy in the 23andMe and ALSPAC cohorts.

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Acknowledgements

We thank the customers of 23andMe who answered surveys, as well as the employees of 23andMe, who together made this research possible. We also thank K. Nadeau for assistance in survey development and S. Nelson and R. Altman for reviewing surveys. This work was supported in part by the National Heart, Lung, and Blood Institute of the US National Institutes of Health under grant 1R43HL115873-01.

We are extremely grateful to all the families who took part in ALSPAC, to the midwives for their help in recruiting them and to the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK MRC (grant 74882), the Wellcome Trust (grant 092731) and the University of Bristol provide core support for ALSPAC.

This publication is the work of the authors, and D.A.H., N.J.T. and J.Y.T. will serve as guarantors for the contents of this paper.

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Authors

Contributions

D.A.H. and G.M. analyzed the data. A.K.K. designed the survey for 23andMe. G.M., D.M.E. and B.S.P. were part of the ALSPAC GWAS preparation team. S.M.R. was responsible for ALSPAC sample collection and preparation. C.B.D. and N.E. developed analytical tools. J.L.M., U.F. and G.D.-S. supervised the project. D.A.H., G.M., N.J.T. and J.Y.T. designed the study and wrote the manuscript.

Corresponding author

Correspondence to David A Hinds.

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Competing interests

D.A.H., A.K.K., C.B.D., N.E., J.L.M., U.F. and J.Y.T. are current or former employees of and own stock or stock options in 23andMe, Inc.

Supplementary information

Supplementary Figures and Tables

Supplementary Figures 1 and 2, Supplementary Tables 2–4, 6–9 and 11–15, and Supplementary Note (PDF 6440 kb)

Supplementary Table 1

Association test results in the 23andMe cohort, the ALSPAC cohort, and the meta-analysis (XLS 2165 kb)

Supplementary Table 5

SNP-SNP interaction test results (XLS 80 kb)

Supplementary Table 10

ENCODE project annotations of allergy loci using HaploReg (XLS 164 kb)

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Hinds, D., McMahon, G., Kiefer, A. et al. A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. Nat Genet 45, 907–911 (2013). https://doi.org/10.1038/ng.2686

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