Meta-analysis of genome-wide association studies of food allergy and IgE-sensitization

BACKGROUND: Food allergies (FA) arise from a complex interplay between an individual's genetic predisposition and environmental factors and their prevalence is increasing. Genome-wide association studies (GWAS) to date have been hindered by small sample sizes and varying FA definitions. OBJECTIVE: Identify novel food allergy risk loci by conducting a GWAS meta-analysis in children and adults using a multi-phenotype approach to ensure the trade-off between sufficient sample size and valid FA definitions. METHODS: Analyses were conducted separately in children and adults based on the following FA phenotypes: self-report, doctors-diagnosis, food-specific sensitization, and doctors-diagnosis plus food-specific sensitization. GWAS from up to 16 cohorts of European ancestry including 229,426 adults and 14,234 children were meta-analyzed. Models were adjusted for sex, age, principal components, and if applicable, further study-specific confounders. Sensitivity models were additionally adjusted for hay fever. Replication was conducted in additional external cohorts and a validation in oral food challenge-defined FA cases. RESULTS: 37 SNPs met suggestive significance (p-value < 1x10(-6)), with two reaching genome-wide significance: rs116936231 (FGL1) in adult doctors-diagnosed FA plus food-specific sensitization phenotype (stable after additional hay fever adjustment) and rs8022829 (AKAP6-NPAS3) which was significant only in the hay fever-adjusted model in adults. However, neither variant was validated. Further, we identified three SNPs previously reported for FA and atopic diseases. CONCLUSION: This study identified 37 SNPs suggestively associated with FA and demonstrated genetic differences across phenotypes. It highlights the need for a unified FA definition and sheds light on its shared genetic architecture with allergies.

• Maier, L.
• Sun, Y.
• Kronberg, J.
• Abner, E.
• Estonian Biobank Research, Team
• Coley, K.
• Marenholz, I.
• Weiss, S.
• Foraita, R.
• Karramass, T.
• Mykkanen, J.
• Hernandez-Pacheco, N.
• Wang, C. A.
• Kitaba, N. T.
• Pechlivanis, S.
• Bouzigon, E.
• Tingskov Pedersen, C. E.
• Schoos, A. M.
• Curtin, J.
• Kress, S.
• Hernangomez-Laderas, A.
• Foppiano, F.
• Ashley, S.
• Batini, C.
• Bryant, L.
• Homuth, G.
• Gieger, C.
• Gilles, S.
• Lyytikainen, L. P.
• Rovio, S.
• Pahkala, K.
• Vernet, R.
• Valenta, R.
• Llop, S.
• Torrent, M.
• Bock, A.
• Tang, M. L. K.
• Schmidt-Weber, C. B.
• Metspalu, A.
• Esko, T.
• Sprikkelman, A. B.
• John, C.
• Lee, Y. A.
• Beyer, K.
• Volzke, H.
• Pigeot, I.
• Traidl-Hoffmann, C.
• Duijts, L.
• Lu, H.
• Raitakari, O. T.
• Lehtimaki, T.
• Kahonen, M.
• Tio, C. H. L.
• Melen, E.
• Pennell, C. E.
• Holloway, J. W.
• von Mutius, E.
• Siroux, V.
• Bonnelykke, K.
• Custovic, A.
• Simpson, A.
• Schikowski, T.
• Bilbao, J. R.
• Schaub, B.
• Peters, R.
• Kersten, E. T. G.
• Vonk, J. M.
• Thiering, E.
• Peters, A.
• Koppelman, G. H.
• Standl, M.