Genome-Wide Association Study to Identify the Genetic Determinants of Otitis Media Susceptibility in Childhood

Background: Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion.Susceptibility to recurrent acute OM (rAOM; $3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE$3 months) is 40–70% heritable. Few underlying genes have been identified to date, and no genome-wide associationstudy (GWAS) of OM has been reported.Methods and Findings: Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPsgenotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive modelundertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs atCAPN14 (rs6755194: OR = 1.90; 95%CI 1.47–2.45; Padj-PCA = 8.361027) on chromosome 2p23.1 as the top hit, withindependent effects (rs1862981: OR = 1.60; 95%CI 1.29–1.99; Padj-PCA = 2.261025) observed at the adjacent GALNT14 gene. Ina gene-based analysis in VEGAS, BPIFA3 (PGene=261025) and BPIFA1 (PGene = 1.0761024) in the BPIFA gene cluster onchromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (Padj-PCA,1025) in thisGWAS, with pathway analysis showing a connection between top candidates and the TGFb pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals)from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size,difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS.