Open Access

Lisa Maier, Yidan Sun, Jaanika Kronberg, Erik Abner, Kayesha Coley, Ingo Marenholz, Stefan Weiss, Ronja Foraita, Tarik Karramass, Juha Mykkänen, Natalia Hernandez-Pacheco, Carol A. Wang, Negusse T. Kitaba, Sonali Pechlivanis, Emmanuelle Bouzigon, Casper E. Tingskov Pedersen, Ann-Marie M. Schoos, John Curtin, Sara Kress, Alba Hernangomez-Laderas, Francesco Foppiano, Sarah Ashley, Chiara Batini, Luke Bryant, Georg Homuth, Christian Gieger, Stefanie Gilles, Leo-Pekka Lyytikäinen, Suvi Rovio, Katja Pahkala, Raphaël Vernet, Rudolph Valenta, Sabrina Llop, Maties Torrent, Andreas Böck, Mimi L. K. Tang, Carsten B. Schmidt-Weber, Andres Metspalu, Tõnu Esko, Aline B. Sprikkelman, Catherine John, Young-Ae Lee, Kirsten Beyer, Henry Völzke, Iris Pigeot, Claudia Traidl-Hoffmann, Liesbeth Duijts, Haojie Lu, Olli T. Raitakari, Terho Lehtimäki, Mika Kähönen, Chris H. L. Tio, Erik Melén, Craig E. Pennell, John W. Holloway, Erika von Mutius, Valérie Siroux, Klaus Bønnelykke, Adnan Custovic, Angela Simpson, Tamara Schikowski, Jose Ramon Bilbao, Bianca Schaub, Rachel Peters, Elin T. G. Kersten, Judith M. Vonk, Elisabeth Thiering, Annette Peters, Gerard H. Koppelman, Marie Standl

• 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 additionallyBackground: 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.…