Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3×10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5×10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.
About The Expert
Manuel A R Ferreira
Judith M Vonk
Hansjörg Baurecht
Ingo Marenholz
Chao Tian
Joshua D Hoffman
Quinta Helmer
Annika Tillander
Vilhelmina Ullemar
Yi Lu
Sarah Grosche
Franz Rüschendorf
Raquel Granell
Ben M Brumpton
Lars G Fritsche
Laxmi Bhatta
Maiken E Gabrielsen
Jonas B Nielsen
Wei Zhou
Kristian Hveem
Arnulf Langhammer
Oddgeir L Holmen
Mari Løset
Gonçalo R Abecasis
Cristen J Willer
Nima C Emami
Taylor B Cavazos
John S Witte
Agnieszka Szwajda
David A Hinds
Norbert Hübner
Stephan Weidinger
Patrik Ke Magnusson
Eric Jorgenson
Robert Karlsson
Lavinia Paternoster
Dorret I Boomsma
Catarina Almqvist
Young-Ae Lee
Gerard H Koppelman
References
PubMed