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

Background: Food allergy (FA) arises from a complex interplay between an individual’s genetic predisposition and environmental factors, and its prevalence is increasing. Genome-wide association studies to date have been hindered by small sample sizes and varying FA definitions. Objective: We sought to identify novel FA risk loci by conducting a genome-wide association study meta-analysis in children and adults by using a multiphenotype approach to ensure a good trade-off between sufficient sample size and valid FA definitions. Methods: Analyses were conducted separately in children and adults on the basis of the following FA phenotypes: self-report, doctor diagnosis, food-specific sensitization, and doctor diagnosis plus food-specific sensitization. A meta-analysis was performed of genome-wide association studies from up to 16 cohorts of people of European ancestry including 229,426 adults and 14,234 children. 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: Thirty-seven single nucleotide polymorphisms met suggestive significance (P < 1 × 10−6), with two reaching genome-wide significance: rs116936231 (FGL1) in adult doctor-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 3 single nucleotide polymorphisms previously reported for FA and atopic disease. Conclusion: This study identified 37 single nucleotide polymorphisms suggestively associated with FA and demonstrated genetic differences across phenotypes. It highlights the need for a unified FA definition and sheds light on FA’s shared genetic architecture with allergies.